Cross-comparison of the genome sequences from human, chimpanzee, Neanderthal and a Denisovan hominin identifies novel potentially compensated mutations

  • Guojie Zhang1Email author,

    Affiliated with

    • Zhang Pei1,

      Affiliated with

      • Edward V Ball2,

        Affiliated with

        • Matthew Mort2,

          Affiliated with

          • Hildegard Kehrer-Sawatzki3 and

            Affiliated with

            • David N Cooper2

              Affiliated with

              Human Genomics20115:453

              DOI: 10.1186/1479-7364-5-5-453

              Received: 22 March 2011

              Accepted: 22 March 2011

              Published: 1 July 2011

              Abstract

              The recent publication of the draft genome sequences of the Neanderthal and a ~50,000-year-old archaic hominin from Denisova Cave in southern Siberia has ushered in a new age in molecular archaeology. We previously cross-compared the human, chimpanzee and Neanderthal genome sequences with respect to a set of disease-causing/disease-associated missense and regulatory mutations (Human Gene Mutation Database) and succeeded in identifying genetic variants which, although apparently pathogenic in humans, may represent a 'compensated' wild-type state in at least one of the other two species. Here, in an attempt to identify further 'potentially compensated mutations' (PCMs) of interest, we have compared our dataset of disease-causing/disease-associated mutations with their corresponding nucleotide positions in the Denisovan hominin, Neanderthal and chimpanzee genomes. Of the 15 human putatively disease-causing mutations that were found to be compensated in chimpanzee, Denisovan or Neanderthal, only a solitary F5 variant (Val1736Met) was specific to the Denisovan. In humans, this missense mutation is associated with activated protein C resistance and an increased risk of thromboembolism and recurrent miscarriage. It is unclear at this juncture whether this variant was indeed a PCM in the Denisovan or whether it could instead have been associated with disease in this ancient hominin.

              Keywords

              Human chimpanzee Neanderthal Denisovan hominin genome sequence potentially compensated mutations disease

              Introduction

              The recent publication of the draft sequence of the Neanderthal genome [1] ushered in a new age in molecular archaeology [2, 3]. This achievement was followed closely by the publication of the draft genome sequence (1.9-fold coverage) of a ~50,000-year old archaic hominin from Denisova Cave in southern Siberia [4]. This hominin (a 'Denisovan') is thought to have been a member of a sister group of hominins to the Neanderthals with whom they lived sympatrically during the Upper Pleistocene [47]. Denisovans appear to be more closely related to Neanderthals than humans, having diverged from Neanderthals about 640,000 years ago and from extant Africans about 804,000 years ago [4].

              Access to DNA sequence data from ancient hominins not only promises to revolutionise our knowledge of hominin relationships, but is also potentially informative in the context of exploring the molecular basis of human genetic disease [8, 9]. We have previously cross-compared the human, chimpanzee and Neanderthal genome sequences with a set of disease-causing/disease-associated missense and regulatory mutations in order to identify genetic variants which, although apparently pathogenic in humans, may represent a 'compensated' wild-type state in at least one of the other two species ('potentially compensated mutations' [PCMs]) [10]. PCMs correspond to variants that may have been deleterious for a certain period of evolutionary time but which persisted long enough in a given population or species to have become positively selected upon the introduction of a 'compensatory' nucleotide change [8, 1114]. Such compensatory changes are thought to be localised in the same gene as the PCM [15]. Not only do PCMs represent excellent candidates for recent population-specific selection (with different alleles having exhibited differential functional importance in different environments), but they may also furnish us with new insights into the genetic basis of susceptibility to common diseases [8, 14]. Here, in an attempt to identify further PCMs of interest, we have compared a dataset of human mutations of putative pathological significance with their corresponding nucleotide positions in the Neanderthal, Denisovan and chimpanzee genomes.

              Methods

              Human Gene Mutation Database (HGMD) dataset

              A total of 46,060 disease-causing (DMs) or disease-associated mutations had been obtained from the HGMD [16]http://​www.​hgmd.​org as of 13th May 2010. These data comprised 44,348 missense mutations from within the coding regions of 2,628 genes, and 1,712 single base-pair substitutions from within the regulatory regions (5' and 3' untranslated/flanking regions) of 807 genes. Some 42,595 of the mutations were disease-causing (41,960 missense and 635 regulatory), whereas 3,465 represented disease-associated or functional polymorphisms (2,388 missense and 1,077 regulatory) (Table 1). The latter were further ascribed to three distinct subcategories: (1) DPs, comprising variants reported to be in statistically significant (p < 0.05) association with a particular human disease state but lacking experimental evidence of functionality -- for example, from expression studies; (2) disease-associated polymorphisms with experimental evidence of functionality (DFPs) such as, for example, altered in vitro gene expression or protein function; (3) FPs that have been shown in vitro or in vivo to affect the structure, function or expression of the gene or gene product but for which no statistically significant disease association has yet been reported (see http://​www.​hgmd.​cf.​ac.​uk/​docs/​poly.​html for further information).
              Table 1

              Missense and regulatory mutations from the HGMD used in this study, categorised by mutation type and putative role in disease aetiology

              Mutation/

              polymorphism

              type

              Type and putative role in disease

              aetiology

               

              DM

              DP

              DFP

              FP

              Total

              Coding sequence

              41,960

              942

              295

              1,151

              44,348

              Regulatory

              635

              340

              391

              346

              1,712

              Total

              42,595

              1,282

              686

              1,497

              46,060

              DM, disease-causing mutation; DP, disease-associated polymorphism lacking functional evidence; DFP, disease-associated polymorphism with functional evidence; FP, polymorphism with functional evidence but lacking a reported disease association as yet.

              Identification of PCMs

              A total of 8,280,851 nucleotide positions at which the Denisovan genome differs from either the human (NCBI36/hg18) or chimpanzee genome were downloaded from the website of the Max Planck Institute for Evolutionary Anthropology http://​bioinf.​eva.​mpg.​de/​download/​DenisovaGenome/​Denisova_​Neandertal_​catalog.​tgz[1, 4]. The human and the Denisovan hominin were found to exhibit the same nucleotide at 7,283,268 positions (87.95 per cent), so that the human-chimpanzee mismatches must have arisen before the divergence of modern humans and Denisovans (termed a 'derived' or 'D' state in the Denisovan). A total of 941,947 positions (11.38 per cent) displayed the same nucleotide in both Denisovan and chimpanzee, suggesting that the respective substitutions were human specific ('ancestral' or 'A' state in the Denisovan). The remaining 55,636 positions, which display different nucleotides in modern humans, Denisovans and chimpanzees, were termed 'undefined' ('N' state). Of the 8,280,851 Denisovan nucleotide positions investigated here, there were 5,205,736 positions at which the Neanderthal was found to differ from at least one of modern human, chimpanzee and Denisovan. From these 5,205,736 sites, we identified 197 sites for which the apparent wild-type nucleotide in Denisovan, Neanderthal or chimpanzee was logged in the HGMD as disease causing or disease associated in modern humans (Table 2). From the remaining 3,075,115 sites, we identified 117 sites for which the apparent wild-type nucleotide in the Denisovan or chimpanzee was logged in the HGMD as disease causing or disease associated in either the Denisovan or chimpanzee (Table 3).
              Table 2

              HGMD-derived mutations identified as PCMs in the Denisovan, Neanderthal and/or chimpanzee genomes

               

              Mutation type and basis of disease aetiology

              Mutation/

              regulatory type

              PCM state

              DM

              DP

              FP

              DFP

              Total

              Coding sequence

              Human

              5/5

              38/43

              11/11

              17/18

              71/77

               

              Neanderthal

              0/0

              1/1

              0/0

              0/0

              1/1

               

              Denisovan

              1/1

              0/0

              0/0

              0/0

              1/1

               

              Ancient

              0/0

              1/1

              2/4

              0/0

              3/5

               

              Chimpanzee

              4/4

              7/8

              2/4

              0/0

              13/16

               

              Denisovan and chimpanzee

              3/3

              4/5

              0/0

              0/0

              7/8

               

              Neanderthal and chimpanzee

              2/2

              4/6

              1/1

              1/1

              8/10

               

              Others

              1/1

              0/1

              0/0

              0/0

              1/2

               

              Total

              16/16

              55/65

              16/20

              18/19

              105/120

              Regulatory

              Human

              0

              23

              10

              13

              46

               

              Neanderthal

              0

              0

              2

              1

              3

               

              Denisovan

              0

              0

              0

              3

              3

               

              Ancient

              0

              2

              0

              1

              3

               

              Chimpanzee

              0

              5

              5

              4

              14

               

              Denisovan and chimpanzee

              0

              4

              1

              1

              6

               

              Neanderthal and chimpanzee

              0

              1

              1

              0

              2

               

              Others

              0

              0

              0

              1

              1

               

              Total

              0

              35

              19

              24

              78

              'Human': The Denisovan nucleotide, Neanderthal nucleotide and chimpanzee nucleotide were identical to a human DM/disease-associated mutation; 'Neanderthal': The Neanderthal nucleotide was identical to the human DM/disease-associated mutation, whereas both the chimpanzee nucleotide and the Denisovan nucleotide were identical to the human wild-type nucleotide; 'Denisovan': The Denisovan nucleotide was identical to the human DM/disease-associated mutation, whereas both the chimpanzee nucleotide and the Neanderthal nucleotide were identical to the human wild-type nucleotide; 'Ancient': Both the Denisovan nucleotide and the Neanderthal nucleotide were identical to the human DM/disease-associated P mutation, whereas the chimpanzee nucleotide was identical to the human wild-type nucleotide. 'Chimpanzee': The chimpanzee nucleotide was identical to the human DM/disease-associated mutation, whereas both the Neanderthal nucleotide and the Denisovan nucleotide were identical to the modern human wild-type nucleotide. 'Denisovan and chimpanzee': Both the Denisovan nucleotide and the chimpanzee nucleotide were identical to the human DM/disease-associated mutation, whereas the Neanderthal nucleotide was identical to the human wild-type nucleotide; 'Neanderthal and chimpanzee': Both the Neanderthal nucleotide and the chimpanzee nucleotide were identical to the human DM/disease-associated mutation, whereas the Denisovan nucleotide was identical to the human wild-type nucleotide. Under coding sequence, 'a/b' means that there were a total number of 'b' mutations, of which 'a' were non-synonymous mutations (there were some synonymous mutations within the coding sequence; eg CM068190, CM077900).

              PCM, potentially compensated mutations; DM, disease-causing mutation; DP, disease-associated polymorphism with functional evidence; FP, polymorphism with functional evidence but lacking a reported disease association as yet; DFP, disease-associated polymorphism with functional evidence.

              Table 3

              HGMD-derived mutations identified as PCMs in the Denisovan genome and/or chimpanzee genome

               

              Mutation type and basis of disease

              aetiology

              Mutation/

              regulatory

              type

              PCM state

              DM

              DP

              FP

              DFP

              Total

              Coding

              sequence

              Ancestral

              5/5

              24/29

              9/9

              5/7

              43/50

               

              Derived

              4/4

              7/7

              4/5

              4/4

              19/20

               

              Denisovan

              0/0

              4/6

              2/2

              0/0

              6/8

               

              Others

              0/0

              1/1

              0/0

              0/0

              1/1

               

              Total

              9/9

              36/43

              15/16

              9/11

              69/79

              Regulatory

              Ancestral

              2

              6

              9

              12

              29

               

              Derived

              1

              2

              1

              2

              6

               

              Denisovan

              0

              1

              0

              2

              3

               

              Total

              3

              9

              10

              16

              38

              Ancestral: Both the Denisovan nucleotide and the chimpanzee nucleotide were identical to the human DM/disease-associated mutation; Derived: The chimpanzee nucleotide was identical to the human DM/disease-associated mutation, whereas the Denisovan nucleotide was identical to the human wild-type nucleotide; Denisovan: The Denisovan nucleotide was identical to the human DM/disease-associated mutation, whereas the chimpanzee nucleotide was identical to the human wild-type nucleotide. Under coding sequence, 'a/b' means there were a total number of 'b' mutations, of which 'a' were non- synonymous mutations.

              PCM, potentially compensated mutations; DM, disease-causing mutation; DP, disease-associated polymorphism with functional evidence; FP, polymorphism with functional evidence but lacking a reported disease association as yet; DFP, disease-associated polymorphism with functional evidence.

              Gene ontology (GO) enrichment analysis

              A GO enrichment analysis of PCM-containing genes against a background of 2,688 human disease-causing genes was performed using the DAVID bioinformatics tool [17]. The statistical significance of a particular GO term was calculated using Fisher's exact test, which was then adjusted to allow for multiple testing by means of the Benjamini-Hochberg correction [18].

              Calculation of Wright's fixation index (FST) values

              The FST measures the proportion of genetic diversity in a subdivided population that is attributable to allele frequency differences between subpopulations. Pairwise FST values have also been used as a measure of genetic distance between populations. In this context, the allele frequencies of polymorphic ancestral PCMs in selected populations were obtained from HapMap http://​hapmap.​ncbi.​nlm.​nih.​gov/​ and pairwise FST values were estimated for each polymorphism using the small sample estimate proposed by Weir and Hill [19]. The significance of individual FST values was then assessed by reference to the empirical distribution of FST among all single nucleotide polymorphisms (SNPs) in HapMap.

              Results and discussion

              Identification of PCMs in the Denisovan, Neanderthal and/or chimpanzee genomes

              A total of 44,348 missense mutations from 2,628 genes and 1,712 putative regulatory mutations from 807 genes, which have been recorded in the HGMD as being either causative of (or associated with) a human inherited disease state, were cross-compared with the corresponding nucleotide positions in the Neanderthal, Denisovan and chimpanzee genomes.

              When the 197 PCMs covered by both the Denisovan and the Neanderthal sequences were considered, these included 129 of 143 PCMs identified in the Neanderthal genome (10/12 DMs, 65/73 DPs, 25/26 FPs, 29/32 DFPs), and 123 (62 per cent) PCMs for which the Denisovan, Neanderthal and chimpanzee wild-type nucleotides were identical to the human disease-causing/disease-associated mutant allele. Of the 117 PCMs covered only by the Denisovan sequence, there were 79 (67.5 per cent) for which both the Denisovan nucleotide and the chimpanzee nucleotide were identical to a human DM/disease-associated mutation. This may be indicative of either a bottleneck effect or selection during the evolution of the modern human lineage. Of the 197 PCMs, there was one mutation that was compensated only in the Neanderthal, one that was compensated only in the Denisovan, five that were compensated in both Neanderthal and Denisovan and 16 that were compensated only in the chimpanzee. There were also 18 mutations that differed between the Neanderthal and the Denisovan, which could imply that such mutations were identical-by-state (Tables 2 and 3).

              Disease-causing PCMs

              There were 16 human DMs that were found to be potentially compensated in the chimpanzee, Denisovan or Neanderthal (covered by both the Neanderthal and the Denisovan sequence) and 12 human DMs potentially compensated in the chimpanzee or Denisovan (covered only by the Denisovan sequence) (Table 4).
              Table 4

              Human DMs identified as PCMs

              Category

              HGMD

              Acc. No

              Chr

              Chrom.

              location

              Strand

              Disease

              Gene

              Mutation

              HGVS (cDNA)

              nomenclature

              HGVS

              (protein)

              nomenclature

              Type

              Covered by

              both the

              Neanderthal

              and the

              Denisovan

              sequencea

              CM993347

              Chr1

              67633930

              +

              Atopy

              IL12RB2

              A > G:GAA

              NM_001559.2:

              c.2159A > G

              NP_001550.1:

              p.H720R

              Chimpanzee

               

              CM042258

              Chr1

              94337039

              -

              Stargardt disease

              ABCA4

              T > G:GGT

              NM_000350.2:

              c.667A > C

              NP_000341.2:

              p.K223Q

              Denisovan

              and

              chimpanzee

               

              CM070090

              Chr1

              167765599

              -

              Thrombosis?

              F5

              C > T:CTC

              NM_000130.4:

              c.5290G > A

              NP_000121.2:

              p.V1764M

              Denisovan

               

              CM099258

              Chr15

              40468491

              +

              Muscular

              dystrophy?

              CAPN3

              G > A:AAA

              NM_000070.2:

              c.706G > A

              NP_000061.1:

              p.A236T

              Human

               

              CM085365*

              Chr15

              43185730

              -

              Hypothyroidism

              DUOX2

              T > C:CCC

              NM_014080.4:

              c.2033A > G

              NP_054799.4:

              p.H678R

              Human

               

              CM984025*

              Chr19

              18047618

              -

              Mycobacterial

              infection

              IL12RB1

              T > C:CCT

              NM_005535.1:

              c.641A > G

              NP_005526.1:

              p.Q214R

              Denisovan

              and

              chimpanzee

               

              CM044918

              Chr19

              41022117

              -

              Congenital

              nephrotic

              syndrome,

              Finnish type

              NPHS1

              C > G:GGG

              NM_004646.1:

              c.2971G > C

              NP_004637.1:

              p.V991L

              Human

               

              CM064230

              Chr19

              43656115

              +

              Malignant

              hyperthermia

              RYR1

              A > G:GAA

              NM_000540.2:

              c.4024A > G

              NP_000531.2:

              p.S1342G

              Chimpanzee

               

              CM961339*

              Chr22

              30836050

              +

              Glucose/galactose

              malabsorption

              SLC5A1

              C > G:GGC

              NM_000343.1:

              c.1845C > G

              NP_000334.1:

              p.H615Q

              Denisovan

              and

              chimpanzee

               

              CM980573

              Chr5

              149341414

              +

              Achondrogenesis

              1B

              SLC26A2

              A > T:TAT

              NM_000112.3:

              c.2065A > T

              NP_000103.2:

              p.T689S

              Neanderthal

              and

              chimpanzee

               

              CM043093

              Chr6

              25958824

              -

              Glycogen storage

              disease 1c?

              SLC17A3

              C > T:TCC

              NM_006632.3:

              c.601G > A

              NP_006623.2:

              p.G201R

              Chimpanzee

               

              CM072814

              Chr7

              86894112

              -

              Intrahepatic

              cholestasis,

              familial

              progressive?

              ABCB4

              T > C:CCC

              NM_000443.3:

              c.1954A > G

              NP_000434.1:

              p.R652G

              Human

               

              CM050323

              Chr7

              107129530

              +

              Pendred

              syndrome?

              SLC26A4

              T > G:GTG

              NM_000441.1:

              c.1826T > G

              NP_000432.1:

              p.V609G

              Neanderthal

              and

              chimpanzee

               

              CM983990

              Chr8

              22032655

              -

              Alopecia

              universalis?

              HR

              T > C:CCC

              NM_005144.3:

              c.3064A > G

              NP_005135.2:

              p.T1022A

              Human

               

              CM099178*

              Chr8

              118899878

              -

              Multiple

              osteochondromas

              EXT1

              C > T:TCC

              NM_000127.2:

              c.1609G > A

              NP_000118.2:

              p.V537I

              Chimpanzee

               

              CM085353*

              ChrX

              149390017

              +

              Hypospadias

              MAMLD1

              T > C:CYC

              NM_005491.2:

              c.1514T > C

              NP_005482.2:

              p.V505A

              Others

              Covered

              only by the

              Denisovan

              sequenceb

              CM043273

              Chr1

              195670491

              +

              Retinitis

              pigmentosa

              CRB1

              G > A:AG

              NM_201253.1:

              c.2875G > A

              NP_957705.1:

              p.G959S

              Chimpanzee

               

              CM067436

              Chr11

              7020956

              +

              Spermatogenic

              failure

              NLRP14

              G > A:AG

              NM_176822.3:

              c.1123G > A

              NP_789792.1:

              p.A375T

              Chimpanzee

               

              CM043536

              Chr11

              47326617

              -

              Cardiomyopathy,

              hypertrophic?

              MYBPC3

              T > C:CT

              NM_000256.3:

              c.706A > G

              NP_000247.2:

              p.S236G

              Chimpanzee

               

              CM082943

              Chr11

              118720796

              -

              Primary

              angle-closure

              glaucoma?

              MFRP

              C > T:TT

              NM_031433.1:

              c.770G > A

              NP_113621.1:

              p.R257H

              Ancestral

               

              CM091988

              Chr12

              32913201

              -

              Arrhythmogenic

              right ventricular

              cardiomyopathy

              PKP2

              A > G:GG

              NM_004572.3:

              c.1097T > C

              NP_004563.2:

              p.L366P

              Ancestral

               

              CM044579

              Chr13

              51413355

              -

              Wilson disease?

              ATP7B

              A > G:GG

              NM_000053.2:

              c.3419T > C

              NP_000044.2:

              p.V1140A

              Ancestral

               

              CM073339

              Chr17

              24310977

              -

              Febrile seizures?

              SEZ6

              T > C:CC

              NM_178860.4:

              c.1636A > G

              NP_849191.3:

              p.T546A

              Ancestral

               

              CM101950

              Chr2

              98363138

              +

              Progressive cone

              dystrophy?

              CNGA3

              C > T:TC

              NM_001298.2:

              c.284C > T

              NP_001289.1:

              p.P95L

              Chimpanzee

               

              CM961335

              Chr22

              30817700

              +

              Glucose/galactose

              malabsorption

              SLC5A1

              G > A:AA

              NM_000343.1:

              c.1231G > A

              NP_000334.1:

              p.A411T

              Ancestral

               

              CR080762

              Chr1

              15645754

              +

              Pancreatitis,

              chronic?

              CTRC

              T > C:CC

              rs75456156:T > C

              NA

              Ancestral

               

              CR080761

              Chr1

              15645757

              +

              Pancreatitis,

              chronic?

              CTRC

              A > G:GG

              rs760937:A > G

              NA

              Ancestral

               

              CR962526

              Chr8

              41774321

              -

              Spherocytosis

              ANK1

              A > G:GA

              rs77173848:A > G

              NA

              Chimpanzee

              aMutation type: modern human wild-type > modern human mutation: chimpanzee nucleotide, Denisovan nucleotide, Neanderthal nucleotide (both Neanderthal and Denisovan sequence covered). Y denotes pyrimidine.

              bModern human wild-type > modern human mutation: chimpanzee nucleotide, Denisovan nucleotide (only Denisovan sequence covered).

              *Previously reported by Zhang et al.[10]

              Of the human DMs that were potentially compensated in the chimpanzee, Denisovan or Neanderthal, only the putatively pathological F5 variant was specific to the Denisovan. In humans, this missense mutation, Val1736Met, is associated with activated protein C resistance and an increased risk of thromboembolism and recurrent miscarriage [20, 21]. It is unclear at this juncture whether this variant was indeed a PCM in the Denisovan or whether it could instead have been associated with disease in this archaic hominin.

              Even though Denisovans appear to be more closely related to Neanderthals than humans, the Neanderthal and Denisovan were discrepant with respect to certain PCMs (eg the SLC5A1 H615Q variant associated with glucose-galactose malabsorption). In this case, the Denisovan (and the chimpanzee) possessed the allele that was mutant in humans (G), whereas the Neanderthal possessed the allele (C) which was wild-type in humans. In this context, it may be pertinent to mention that SLC5A1 is located on chromosome 22q12.3 within a region of putative gene flow from Neanderthal to Eurasian [1].

              Some of the PCMs listed in Table 4 may well have been misclassified by the original authors as disease-causing in human (especially those variants which have been allocated a '?' by the HGMD; see Table 4) when they were actually neutral polymorphisms; however, this is much less likely in the case of the 16 human disease-causing mutations that are covered by both the Neanderthal and Denisovan sequences. These mutant alleles would have had to have been maintained in both Neanderthal and Denisovan populations for ~640,000 years, when these two hominins last shared a common ancestor, and this would have been unlikely if such variants had been neutral polymorphisms.

              Statistically enriched GO terms were identified for genes containing human DMs identified as PCMs (Table 4) against a background of known disease-causing genes (from the HGMD) and are shown in Table S1 (Table 6). Five significantly enriched GO terms were found; all relate to the plasma membrane.
              Table S1

              Significantly enriched GO terms (Benjamini-corrected p-value <0.05) for human genes containing DMs identified as PCMs (listed in Table 4) against a background of known disease-causing genes. No significantly enriched GO terms were found to relate to biological processes or molecular function

              GO Term

              Category

              Description

              Fold

              enrichment

              p-Value

              Genes

              GO:0031224

              Cellular component

              Intrinsic to

              membrane

              2.12

              4.29E-03

              SLC5A1, DUOX2, CNGA3, ABCA4, SLC26A2, MFRP, ABCB4,

              IL12RB2, SLC26A4, IL12RB1, CRB1, SLC17A3, PKP2, NPHS1,

              RYR1, EXT1, SEZ6, ATP7B

              GO:0016021

              Cellular component

              Integral to membrane

              2.21

              4.59E-03

              SLC5A1, DUOX2, CNGA3, ABCA4, SLC26A2, MFRP, ABCB4,

              IL12RB2, SLC26A4, IL12RB1, CRB1, SLC17A3, PKP2, NPHS1,

              RYR1, EXT1, SEZ6, ATP7B

              GO:0005886

              Cellular component

              Plasma membrane

              2.17

              5.49E-03

              SLC5A1, DUOX2, ABCA4, SLC26A2, ABCB4, IL12RB2, SLC26A4,

              IL12RB1, ANK1, CRB1, SLC17A3, F5, PKP2, NPHS1, RYR1, SEZ6,

              ATP7B

              GO:0031226

              Cellular component

              Intrinsic to plasma

              membrane

              3.02

              3.92E-02

              IL12RB2, IL12RB1, SLC17A3, SLC5A1, NPHS1, RYR1, ABCA4,

              SLC26A2, ATP7B, ABCB4

              GO:0005887

              Cellular component

              Integral to plasma

              membrane

              3.11

              3.93E-02

              IL12RB2, IL12RB1, SLC17A3, SLC5A1, NPHS1, RYR1, ABCA4,

              SLC26A2, ATP7B, ABCB4

              With respect to the DPs/FPs, 100 DPs, 39 FPs and 43 DFPs were covered by both the Neanderthal and Denisovan sequences (Table S2 (Table 7)), while 52 DPs, 26 FPs and 27 DFPs were covered by the Denisovan but not the Neanderthal sequence (Table S3 (Table 8)); these DPs/FPs may be relevant to human genetic disease.
              Table S2

              PCMs covered by both the Denisovan sequence and the Neanderthal sequence

              HGMD

              Acc

              Chr

              Location

              Strand

              Tag

              Disease

              Gene

              Mutation

              AA seq

              Type

              CM031993

              Chr1

              9246497

              +

              DFP

              Cortisone reductase

              deficiency, partial

              H6PD

              G > A:AAA

              Arg-Gln

              Human

              CM040788

              Chr1

              11828655

              -

              DP

              Stroke, increased

              risk, association with

              NPPA

              A > G:GGG

              Term-Arg

              Human

              CM100611

              Chr1

              12005513

              +

              DFP

              Breast cancer,

              reduced risk,

              association with

              MIIP

              A > G:GGG

              Lys-Glu

              Human

              CM980072

              Chr1

              21767322

              +

              DFP

              Hypophosphatasia,

              association with

              ALPL

              T > C:CCC

              Tyr-His

              Human

              CM056598

              Chr1

              31865112

              +

              DP

              Polydipsia-

              hyponatraemia,

              association with

              HCRTR1

              A > G:GAA

              Ile-Val

              Chimpanzee

              CM994122

              Chr1

              35033356

              +

              DFP

              Atherosclerosis,

              association with

              GJA4

              C > T:TTT

              Pro-Ser

              Human

              CM065514

              Chr1

              55410663

              -

              DP

              Parkinson's disease,

              risk, association with

              USP24

              G > A:AAA

              Thr-Ile

              Human

              CM073141

              Chr1

              67457975

              +

              DP

              Psoriasis, increased

              risk, association with

              IL23R

              T > C:CCC

              Leu-Pro

              Human

              CM993347

              Chr1

              67633930

              +

              DM

              Atopy

              IL12RB2

              A > G:GAA

              His-Arg

              Chimpanzee

              CM067986

              Chr1

              86873963

              +

              DP

              Chloride channel

              deficiency,

              association with

              CLCA3P

              C > G:GGG

              Tyr-Term

              Human

              CM042258

              Chr1

              94337039

              -

              DM

              Stargardt disease

              ABCA4

              T > G:GGT

              Lys-Gln

              Denisova

              and

              chimpanzee

              CM067656

              Chr1

              156491643

              +

              DP

              Guillain-Barre '

              syndrome, reduced

              risk, association

              with?

              CD1A

              C > G:GGC

              Cys-Trp

              Denisova

              and

              chimpanzee

              CM070090

              Chr1

              167765599

              -

              DM

              Thrombosis?

              F5

              C > T:CTC

              Val-Met

              Denisovan

              CM099896

              Chr1

              173615346

              -

              DP

              Schizophrenia,

              association with

              TNR

              C > T:TTT

              Arg-Lys

              Human

              CM023569

              Chr1

              199313698

              -

              DP

              Hypokalaemic

              periodic paralysis,

              association with?

              CACNA1S

              G > A:GRA

              Gly-Gly

              Unsure

              CM920010

              Chr1

              228912417

              -

              DP

              Hypertension,

              association with

              AGT

              A > G:GGG

              Met-Thr

              Human

              CM065155

              Chr1

              240108924

              +

              DP

              Colorectal cancer,

              increased risk,

              association with

              EXO1

              G > A:AAA

              Glu-Lys

              Human

              CM033447

              Chr10

              42926693

              +

              DP

              Hirschsprung

              disease, association

              with

              RET

              A > G:GGG

              Ala-Ala

              Human

              CM068190

              Chr10

              54198272

              -

              FP

              Increased serum

              mannose-binding

              lectin (MBL) level,

              association with?

              MBL2

              C > G:CGG

              Leu-Leu

              Ancient

              CM033482

              Chr10

              64085190

              +

              DP

              Uric acid

              nephrolithiasis,

              association with

              znf365d

              G > A:GGA

              Ala-Thr

              Neanderthal

              CM067461

              Chr10

              81691702

              -

              DP

              Lung cancer,

              susceptibility to,

              association with

              SFTPD

              T > C:CCC

              Thr-Ala

              Human

              CM035804

              Chr11

              524242

              -

              DP

              Bladder cancer,

              association with?

              HRAS

              A > G:GAG

              His-His

              Neanderthal

              and

              chimpanzee

              CM025891

              Chr11

              74585230

              +

              FP

              Decreased enzyme

              activity, association

              with

              SLCO2B1

              C > T:TTT

              Ser-Phe

              Human

              CM080415

              Chr11

              113308238

              +

              FP

              Altered receptor

              function, association

              with

              HTR3B

              A > C:CCC

              Tyr-Ser

              Human

              CM950862

              Chr12

              5473868

              +

              DP

              Schizophrenia,

              severe, increased

              risk, association with

              NTF3

              G > A:AGG

              Gly-Glu

              Chimpanzee

              CM093840

              Chr12

              6023795

              -

              DP

              von Willebrand

              disease, quantitative

              type, association

              with

              VWF

              T > C:CCC

              Thr-Ala

              Human

              CM994637

              Chr12

              6327323

              -

              DFP

              Hypertension,

              reduced risk,

              association with

              SCNN1A

              T > C:CCC

              Thr-Ala

              Human

              CM003671

              Chr12

              14884706

              -

              FP

              Dombrock blood

              group variation

              ART4

              T > C:TCC

              Asn-Asp

              Ancient

              CM077900

              Chr12

              70659129

              +

              FP

              Increased mRNA

              expression,

              association with?

              TPH2

              G > A:GAA

              Pro-Pro

              Ancient

              CM085048

              Chr12

              78539038

              -

              DP

              Schizophrenia in

              females, association

              with

              PAWR

              A > C:CCC

              Ile-Met

              Human

              CM033453

              Chr12

              107542027

              -

              DFP

              Coronary heart

              disease, decreased

              risk, in African

              Americans,

              association with

              SELPLG

              C > T:TTT

              Met-Ile

              Human

              CM022034

              Chr13

              32526193

              +

              DP

              Age-related

              phenotypes,

              association with

              KL

              G > C:CGG

              Cys-Ser

              Chimpanzee

              CM033777

              Chr14

              24170122

              -

              DP

              Apoptosis, unable to

              induce, association

              with

              GZMB

              A > G:GGG

              Tyr-His

              Human

              CM070246

              Chr14

              60993992

              +

              DFP

              Cerebral infarction,

              association with

              PRKCH

              G > A:AAA

              Val-Ile

              Human

              CM067476

              Chr15

              41511938

              -

              DP

              Lung cancer,

              susceptibility to,

              association with

              TP53BP1

              T > G:GGG

              Lys-Gln

              Human

              CM067475

              Chr15

              41555066

              -

              DP

              Lung cancer,

              susceptibility to,

              association with

              TP53BP1

              G > C:CCC

              Asp-Glu

              Human

              CM085365

              Chr15

              43185730

              -

              DM

              Hypothyroidism

              DUOX2

              T > C:CCC

              His-Arg

              Human

              CM054862

              Chr15

              46213776

              +

              DP

              Increased skin

              pigmentation,

              association with

              SLC24A5

              A > G:GGG

              Thr-Ala

              Human

              CM057869

              Chr15

              76704628

              -

              FP

              Altered function,

              association with

              CHRNB4

              T > C:CTT

              Met-Val

              Chimpanzee

              CM031698

              Chr15

              97295748

              +

              DP

              Increased longevity,

              association with?

              IGF1R

              G > A:AGG

              Glu-Glu

              Chimpanzee

              CM057585

              Chr16

              1442858

              -

              DP

              Lower femoral neck

              bone mineral density

              in women,

              association with

              CLCN7

              C > T:TCT

              Val-Met

              Neanderthal

              and

              chimpanzee

              CM983400

              Chr16

              27263704

              +

              DFP

              Asthma, atopic,

              association with

              IL4R

              A > G:GGG

              Ile-Val

              Human

              CM067985

              Chr16

              87788983

              +

              DP

              Cadherin deficiency,

              association with

              CDH15

              C > A:AAA

              Tyr-Term

              Human

              CM057933

              Chr17

              4585312

              -

              DP

              Atherosclerotic

              stenosis, increased,

              association with

              CXCL16

              G > A:AAG

              Ala-Val

              Denisova

              and

              chimpanzee

              CM077855

              Chr17

              7532893

              +

              DP

              Breast cancer,

              oestrogen receptor

              (ER) negative,

              association with?

              WRAP53

              C > G:GGG

              Arg-Gly

              Human

              CM087381

              Chr17

              7987497

              -

              FP

              Increased sex

              hormone-binding

              globulin levels,

              association with

              PER1

              C > G:GGG

              Ala-Pro

              Human

              CM067489

              Chr17

              16468520

              -

              DP

              Lung cancer,

              susceptibility to,

              association with

              ZNF624

              C > A:AAA

              Lys-Asn

              Human

              CM030773

              Chr17

              19753133

              -

              DP

              Cardiac disease,

              susceptibility to,

              association with

              AKAP10

              T > C:CCC

              Ile-Val

              Human

              CM067336

              Chr17

              19802050

              -

              DP

              Lung cancer,

              susceptibility to,

              association with

              AKAP10

              C > T:TTT

              Arg-His

              Human

              CM096315

              Chr17

              38498462

              -

              DFP

              Cervical cancer,

              decreased risk,

              association with

              BRCA1

              G > A:AAA

              Pro-Leu

              Human

              CM093418

              Chr17

              39581073

              +

              DP

              Hip bone mineral

              density, association

              with?

              C17orf53

              A > C:CCC

              Thr-Pro

              Human

              CM032397

              Chr17

              41432502

              +

              DP

              Progressive

              supranuclear palsy,

              association with

              STH

              A > G:GAA

              Gln-Arg

              Chimpanzee

              CM064363

              Chr17

              45788957

              +

              DP

              Organ involvement

              in pseudoxantnoma

              elasticum (PXE),

              association with

              XYLT2

              T > C:CCC

              Tyr-Tyr

              Human

              CM092499

              Chr17

              76468818

              +

              FP

              Altered splicing,

              association with?

              KIAA1303

              A > G:GAA

              Gln-Gln

              Chimpanzee

              CM080431

              Chr19

              11091881

              +

              FP

              Increased plasma

              low-density

              lipoprotein

              cholesterol,

              association with

              LDLR

              T > C:CTT

              Val-Val

              Chimpanzee

              CM984025

              Chr19

              18047618

              -

              DM

              Mycobacterial

              infection

              IL12RB1

              T > C:CCT

              Gln-Arg

              Denisova

              and

              chimpanzee

              CM044918

              Chr19

              41022117

              -

              DM

              Congenital nephrotic

              syndrome, Finnish

              type

              NPHS1

              C > G:GGG

              Val-Leu

              Human

              CM073386

              Chr19

              50087554

              +

              DP

              Alzheimer's disease,

              late-onset,

              association with?

              TOMM40

              T > C:CCC

              Phe-Phe

              Human

              CM004814

              Chr19

              50546759

              -

              DFP

              Basal cell carcinoma,

              reduced risk,

              association with

              ERCC2

              T > G:GGG

              Lys-Gln

              Human

              CM096319

              Chr2

              11276571

              -

              DP

              Chronic kidney

              disease in individuals

              with low

              triglycerides,

              association with

              ROCK2

              G > T:TGT

              Thr-Asn

              Neanderthal

              and

              chimpanzee

              CM052876

              Chr2

              49043425

              -

              DP

              Menstrual cycle

              length, association

              with

              FSHR

              C > T:TTT

              Ser-Asn

              Human

              CM073086

              Chr2

              85634047

              -

              DP

              Higher body mass

              index, association

              with

              GGCX

              C > T:TCC

              Arg-Gln

              Chimpanzee

              CM087379

              Chr2

              100957736

              +

              FP

              Higher testosterone

              levels, association

              with

              NPAS2

              A > G:GGG

              Thr-Ala

              Human

              CM004559

              Chr2

              227369287

              -

              DP

              Diabetes, type 2,

              association with

              IRS1

              T > C:CCT

              Ala-Ala

              Denisova

              and

              chimpanzee

              CM085146

              Chr2

              227839413

              +

              DP

              Chronic obstructive

              pulmonary disease,

              association with

              COL4A3

              A > G:GAA

              His-Arg

              Chimpanzee

              CM014824

              Chr20

              4653718

              +

              DP

              Creutzfeldt-Jakob

              disease, association

              with

              PRND

              C > T:TCT

              Thr-Met

              Neanderthal

              and

              chimpanzee

              CM064121

              Chr20

              44075813

              +

              DP

              Leukaemia, risk,

              association with

              MMP9

              G > C:CCC

              Arg-Pro

              Human

              CM035699

              Chr21

              14403236

              -

              FP

              Plasma high-density

              lipoprotein (HDL)

              cholesterol,

              association with

              LIPI

              G > T:TTT

              Asp-Glu

              Human

              CM057711

              Chr21

              33536125

              +

              DP

              Multiple sclerosis,

              susceptibility to,

              association with

              IFNAR2

              T > G:GGG

              Phe-Val

              Human

              CM025479

              Chr21

              44534334

              +

              DP

              Alopecia universalis,

              association with

              AIRE

              C > G:GGG

              Ser-Arg

              Human

              CM057927

              Chr22

              21957369

              +

              DP

              Bipolar disorder,

              association with?

              BCR

              A > G:GGG

              Asn-Ser

              Human

              CM065332

              Chr22

              24489289

              +

              DP

              Colorectal cancer,

              increased risk,

              association with

              MYO18B

              G > A:AAA

              Gly-Glu

              Human

              CM961339

              Chr22

              30836050

              +

              DM

              Glucose/galactose

              malabsorption

              -SLC5A1

              C > G:GGC

              His-Gln

              Denisova

              and

              chimpanzee

              CM096696

              Chr22

              35792882

              -

              DP

              Iron status and

              erythrocyte volume,

              association with

              TMPRSS6

              A > G:GGG

              Val-Ala

              Human

              CM092918

              Chr22

              37827350

              +

              FP

              Increased

              antiretroviral activity,

              association with

              APOBEC3H

              G > C:CCC

              Gly-Arg

              Human

              CM910052

              Chr22

              49410905

              -

              DP

              Phenotype modifier,

              association with?

              ARSA

              G > C:CCC

              Thr-Ser

              Human

              CM023348

              Chr3

              336508

              +

              DP

              Schizophrenia,

              association with

              CHL1

              C > T:TTT

              Leu-Phe

              Human

              CM096382

              Chr3

              46476217

              -

              DFP

              Periodontitis,

              aggressive,

              association with

              LTF

              T > C:CCC

              Lys-Arg

              Human

              CM066581

              Chr3

              126109714

              -

              DP

              Ulcerative colitis,

              association with

              MUC13

              T > G:GGG

              Arg-Ser

              Human

              CM941277

              Chr3

              172214994

              -

              DP

              Diabetes, type 2,

              association with

              SLC2A2

              G > A:AAG

              Thr-Ile

              Denisova

              and

              chimpanzee

              CM065290

              Chr3

              187925712

              +

              DP

              Nephropathy,

              reduced risk,

              association with

              KNG1

              T > C:CCC

              Met-Thr

              Human

              CM025429

              Chr4

              2960297

              +

              FP

              Increased enzymatic

              activity, association

              with

              GRK4

              G > T:TTT

              Arg-Leu

              Human

              CM094340

              Chr4

              38476105

              -

              DFP

              Leprosy, association

              with

              TLR1

              T > C:CCC

              Asn-Ser

              Human

              CM890003

              Chr4

              100458342

              -

              FP

              Alcohol

              dehydrogenase beta

              variant

              ADH1B

              T > C:CCC

              His-Arg

              Human

              CM092574

              Chr4

              123756413

              -

              DFP

              Asthma, atopic,

              association with

              IL21

              G > A:AAA

              Cys-Cys

              Human

              CM031390

              Chr4

              141708518

              -

              DP

              Waist-to-hip ratio,

              association with

              UCP1

              C > T:TTT

              Ala-Thr

              Human

              CM004732

              Chr5

              1464412

              -

              DP

              Parkinson's disease,

              protection against,

              association with?

              SLC6A3

              T > C:CTC

              Ser-Ser

              Neanderthal

              and

              chimpanzee

              CM094298

              Chr5

              96165006

              -

              DFP

              Cervical carcinoma

              survival, association

              with

              ERAP1

              C > G:GGG

              Arg-Pro

              Human

              CM0910115

              Chr5

              131424377

              +

              DP

              Graves disease,

              association with

              IL3

              C > T:TTT

              Pro-Ser

              Human

              CM043093

              Chr6

              25958824

              -

              DM

              Glycogen storage

              disease 1c?

              SLC17A3

              C > T:TCC

              Gly-Arg

              Chimpanzee

              CM074911

              Chr6

              39433056

              -

              DP

              Coronary heart

              disease, association

              with

              KIF6

              A > G:GGG

              Trp-Arg

              Human

              CM020385

              Chr6

              74550153

              +

              FP

              Gov platelet antigen

              variation

              CD109

              A > C:CCC

              Tyr-Ser

              Human

              CM993455

              Chr6

              132214061

              +

              DFP

              Insulin resistance,

              association with

              ENPP1

              A > C:CCC

              Lys-Gln

              Human

              CM060415

              Chr6

              150156438

              +

              FP

              Reduced stability,

              association with

              PCMT1

              A > G:AGG

              Ile-Val

              Ancient

              CM072043

              Chr6

              160462998

              +

              FP

              Reduced metformin

              uptake, association

              with

              SLC22A1

              C > T:TCC

              Ser-Phe

              Chimpanzee

              CM005460

              Chr7

              17345635

              +

              FP

              Higher induced

              cytochrome P-450

              (CYP) 1A1 activity,

              association with

              AHR

              G > A:AAA

              Arg-Lys

              Human

              CM055287

              Chr7

              45899194

              +

              DP

              Renal function in

              diabetes, association

              with

              IGFBP1

              A > G:GGA

              Ile-Met

              Denisova

              and

              chimpanzee

              CM072814

              Chr7

              86894112

              -

              DM

              Intrahepatic

              cholestasis, familial

              progressive?

              ABCB4

              T > C:CCC

              Arg-Gly

              Human

              CM064968

              Chr7

              91468556

              +

              DP

              Colorectal cancer,

              increased risk,

              association with

              AKAP9

              G > T:TTT

              Met-Ile

              Human

              CM930596

              Chr7

              94775382

              -

              DFP

              Longevity, association

              with

              PON1

              T > C:CCC

              Gln-Arg

              Human

              CM050323

              Chr7

              107129530

              +

              DM

              Pendred syndrome?

              SLC26A4

              T > G:GTG

              Val-Gly

              Neanderthal

              and

              chimpanzee

              CM060083

              Chr7

              122422409

              -

              DP

              Alcohol dependence,

              risk, association with

              TAS2R16

              A > C:CAA

              Asn-Lys

              Chimpanzee

              CM031370

              Chr7

              141319073

              -

              DP

              Phenylthiocarbamide

              taste sensitivity,

              association with

              TAS2R38

              T > C:CCC

              Ile-Val

              Human

              CM031368

              Chr7

              141319814

              -

              DP

              Phenylthiocarbamide

              taste sensitivity,

              association with

              TAS2R38

              C > G:GGG

              Ala-Pro

              Human

              CM081694

              Chr8

              6466450

              +

              DP

              Cranial volume,

              association with

              MCPH1

              C > T:TTT

              Ala-Val

              Human

              CM024569

              Chr8

              18124476

              +

              FP

              Increased enzymatic

              activity, association

              with

              NAT1

              T > G:GTG

              Ser-Ala

              Neanderthal

              and

              chimpanzee

              CM983990

              Chr8

              22032655

              -

              DM

              Alopecia universalis?

              HR

              T > C:CCC

              Thr-Ala

              Human

              CM057431

              Chr8

              27518398

              -

              DP

              Preeclampsia &

              essential

              hypertension,

              association with?

              CLU

              A > G:GGG

              His-His

              Human

              CM950017

              Chr8

              37942955

              -

              DFP

              Hyperinsulinaemia,

              association with

              ADRB3

              A > G:GGG

              Trp-Arg

              Human

              CM099178

              Chr8

              118899878

              -

              DM

              Multiple

              osteochondromas

              EXT1

              C > T:TCC

              Val-Ile

              Chimpanzee

              CM081761

              Chr8

              143758933

              +

              DFP

              Gastric cancer,

              diffuse-type,

              association with

              PSCA

              C > T:TTT

              Thr-Met

              Human

              CM094855

              Chr9

              14712477

              -

              DP

              Low bone mineral

              density, association

              with

              CER1

              G > C:CGC

              Ala-Gly

              Neanderthal

              and

              chimpanzee

              CM940804

              Chr9

              34639442

              +

              DFP

              Galactosaemia,

              Duarte variant

              GALT

              A > G:GAG

              Asn-Asp

              Neanderthal

              and

              chimpanzee

              CM071685

              Chr9

              89511843

              +

              DP

              Inactivation of

              extracellular

              signal-regulated

              kinase (ERK)-induced

              apoptosis,

              association with

              DAPK1

              A > G:AGG

              Asn-Ser

              Ancient

              CM990005

              Chr9

              106626574

              -

              FP

              Higher plasma HDL

              cholesterol,

              association with

              ABCA1

              T > C:CCC

              Ile-Met

              Human

              CM0910114

              ChrX

              77414973

              -

              DP

              Asthma, association

              with

              CYSLTR1

              G > A:AAA

              Phe-Phe

              Human

              CM085353

              ChrX

              149390017

              +

              DM

              Hypospadias

              MAMLD1

              T > C:CYC

              Val-Ala

              Unsure

              CR043164

              Chr1

              43575707

              +

              DP

              Platelet count,

              association with?

              MPL

              C > A:AAA

               

              Human

              CR060579

              Chr1

              111020443

              -

              DP

              Low insulin

              sensitivity,

              association with

              KCNA3

              T > C:TCC

               

              Ancient

              CR057791

              Chr1

              111571946

              +

              FP

              Increased promoter

              activity, association

              with

              CHI3L2

              G > T:GGT

               

              Neanderthal

              CR031479

              Chr1

              170894121

              +

              DFP

              Systemic lupus

              erythematosus (SLE),

              association with

              FASLG

              C > T:TTT

               

              Human

              CR025943

              Chr1

              228917021

              -

              DP

              Increased

              angiotensinogen

              levels, association

              with?

              AGT

              G > A:AGG

               

              Chimpanzee

              CR102882

              Chr10

              64279946

              -

              DFP

              SLE, association with

              EGR2

              C > T:TCC

               

              Chimpanzee

              CR102883

              Chr10

              64280724

              -

              DFP

              SLE, association with

              EGR2

              T > C:CTT

               

              Chimpanzee

              CR072313

              Chr10

              94452862

              +

              DP

              Diabetes, type 2,

              association with?

              HHEX

              C > T:TCC

               

              Chimpanzee

              CR942079

              Chr10

              104587142

              -

              DP

              Polycystic ovaries,

              association with

              CYP17A1

              A > G:GGG

               

              Human

              CR012509

              Chr11

              34416293

              +

              DP

              Hypertension,

              susceptibility to,

              association with

              CAT

              G > A:AGA

               

              Neanderthal

              and

              chimpanzee

              CR072303

              Chr11

              44212190

              +

              DP

              Diabetes, type 2,

              reduced risk,

              association with?

              EXT2

              C > T:CTT

               

              Ancient

              CR035965

              Chr11

              45863406

              +

              DFP

              Alzheimer's disease,

              association with

              MAPK8IP1

              A > G:GGG

               

              Human

              CR094845

              Chr11

              74539529

              +

              FP

              Increased mRNA

              expression,

              association with

              SLCO2B1

              G > A:AAA

               

              Human

              CR045957

              Chr11

              102101690

              -

              DFP

              Preterm premature

              rupture of

              membranes,

              association with?

              MMP8

              G > A:GGA

               

              Neanderthal

              CR025510

              Chr11

              102331749

              -

              FP

              Increased

              transcriptional

              activity, association

              with

              MMP13

              C > T:TCC

               

              Chimpanzee

              CR031478

              Chr12

              10203556

              -

              DP

              Alzheimer disease,

              reduced risk,

              association with

              OLR1

              G > A:AAG

               

              Denisova

              and

              chimpanzee

              CR082031

              Chr12

              55796928

              -

              DP

              Schistosomiasis

              infection, association

              with

              STAT6

              C > T:TTT

               

              Human

              CR087739

              Chr13

              42046024

              +

              DFP

              Bone mineral density

              in osteoporosis,

              association with?

              TNFSF11

              C > T:CTC

               

              Denisovan

              CR080758

              Chr13

              45577313

              -

              FP

              Increased promoter

              activity, association

              with

              CPB2

              T > C:CTT

               

              Chimpanzee

              CR994765

              Chr13

              112807756

              +

              DFP

              Reduced plasma F7

              levels, association

              with

              F7

              G > T:CTT

               

              Unsure

              CR066661

              Chr15

              49336891

              -

              DP

              Alzheimer's disease

              in apolipoprotein E4

              (APOE4) carriers,

              increased risk,

              association with

              CYP19A1

              G > A:AAA

               

              Human

              CR002154

              Chr15

              56511231

              +

              DP

              Dyslipidaemia and

              insulin resistance,

              association with

              LIPC

              G > A:AGG

               

              Chimpanzee

              CR993820

              Chr15

              72828970

              +

              DFP

              Increased activity in

              smokers, association

              with

              CYP1A2

              C > A:AAA

               

              Human

              CR102187

              Chr16

              13921167

              +

              DFP

              Bladder cancer,

              increased risk,

              association with

              ERCC4

              A > C:CAA

               

              Chimpanzee

              CR066332

              Chr16

              54244319

              +

              DFP

              Attention-deficit

              hyperactivity

              disorder, association

              with

              SLC6A2

              A > T:ATA

               

              Denisovan

              CR000229

              Chr16

              55552737

              +

              DFP

              Higher HDL

              cholesterol level,

              association with

              CETP

              C > A:AAA

               

              Human

              CR084012

              Chr17

              25549137

              -

              FP

              Increased expression,

              association with

              SLC6A4

              A > C:CCC

               

              Human

              CR035881

              Chr17

              29706729

              +

              FP

              Increased monocyte

              chemoattractant

              protein-4 (MCP-4)

              plasma levels,

              association with

              CCL13

              C > T:CCT

               

              Neanderthal

              CR003707

              Chr17

              31231893

              -

              DFP

              Atopic dermatitis,

              association with

              CCL5

              C > T:TTT

               

              Human

              CR078280

              Chr17

              35323475

              -

              DP

              Asthma, increased

              risk, association

              with?

              GSDMB

              C > T:TTC

               

              Denisova

              and

              chimpanzee

              CR090198

              Chr17

              38531642

              -

              FP

              Promoter activity,

              association with

              BRCA1

              T > C:CCC

               

              Human

              CR052976

              Chr17

              43163827

              +

              DP

              Asthma,

              aspirin-induced,

              association with

              TBX21

              T > C:CCC

               

              Human

              CR084013

              Chr17

              43178034

              +

              DP

              Genital herpes

              simplex virus-2

              (HSV-2) infection,

              association with?

              TBX21

              G > A:AAA

               

              Human

              CR051707

              Chr19

              7718733

              -

              DFP

              Dengue disease,

              protection against,

              association with

              CD209

              A > G:GGG

               

              Human

              CR095376

              Chr19

              40464739

              +

              DP

              Increased liver iron

              concentration

              HAMP

              A > G:GGA

               

              Denisova

              and

              chimpanzee

              CR050427

              Chr19

              46188969

              +

              FP

              CYP2B6 expression,

              association with

              CYP2B6

              T > C:CCC

               

              Human

              CR051274

              Chr19

              54149750

              +

              DFP

              Disease progression,

              chronic lymphocytic

              leukaemia,

              association with

              BAX

              G > A:GAG

               

              Denisovan

              CR010588

              Chr19

              60077416

              +

              DP

              Immunoglobulin A

              nephropathy,

              association with

              FCAR

              T > C:CCC

               

              Human

              CR051277

              Chr2

              69468799

              -

              DP

              Obesity, association

              with

              GFPT1

              C > T:TTT

               

              Human

              CR025220

              Chr2

              234330398

              +

              DFP

              Hyperbilirubinaemia,

              association with

              UGT1A1

              T > G:GGG

               

              Human

              CR075263

              Chr20

              17370063

              +

              DP

              Diabetes, type 2,

              association with

              PCSK2

              T > C:CCC

               

              Human

              CR077665

              Chr20

              44066518

              +

              FP

              Increased expression,

              association with?

              MMP9

              C > T:TTT

               

              Human

              CR078166

              Chr21

              33619134

              +

              FP

              Increased expression,

              association with

              IFNAR1

              T > C:CCT

               

              Denisova

              and

              chimpanzee

              CR054260

              Chr21

              38590628

              +

              FP

              Promoter activity,

              association with

              KCNJ15

              T > G:GTT

               

              Chimpanzee

              CR096274

              Chr21

              42492734

              +

              DFP

              Coronary artery

              disease, severity,

              association with

              ABCG1

              T > G:GGT

               

              Denisova

              and

              chimpanzee

              CR032439

              Chr3

              12328198

              +

              DFP

              Increased height/lipid

              metabolism,

              association with

              PPARG

              C > G:GGG

               

              Human

              CR066664

              Chr3

              129680794

              -

              DP

              Coronary artery

              disease, association

              with

              GATA2

              G > A:AGG

               

              Chimpanzee

              CR014438

              Chr3

              185572960

              -

              DP

              Myocardial infarction,

              association with

              THPO

              C > T:TTT

               

              Human

              CR004797

              Chr4

              26101320

              -

              DP

              Higher percentage

              body fat, association

              with

              CCKAR

              C > A:ACC

               

              Chimpanzee

              CR045948

              Chr4

              69995928

              +

              FP

              Promoter activity,

              association with

              UGT2B7

              G > A:AAA

               

              Human

              CR025435

              Chr4

              111053559

              +

              DFP

              Malignant melanoma,

              association with

              EGF

              A > G:GGG

               

              Human

              CR057903

              Chr4

              155703465

              +

              DFP

              Cerebral infarction,

              association with

              FGB

              C > T:TTT

               

              Human

              CR071281

              Chr4

              156348632

              +

              DP

              Obesity, association

              with

              NPY2R

              C > T:TTT

               

              Human

              CR071289

              Chr5

              1499389

              -

              DP

              Attention-deficit

              hyperactivity

              disorder, association

              with

              SLC6A3

              A > G:GGG

               

              Human

              CR086597

              Chr5

              110434641

              +

              FP

              Increased promoter

              activity, association

              with

              TSLP

              C > T:TCC

               

              Chimpanzee

              CR035513

              Chr5

              131436741

              +

              DP

              Reduced severity in

              atopic dermatitis,

              association with

              CSF2

              A > C:CCC

               

              Human

              CR015845

              Chr5

              132020708

              +

              DP

              Asthma, association

              with

              IL13

              C > T:TTC

               

              Denisova

              and

              chimpanzee

              CR082018

              Chr6

              78227843

              -

              DFP

              Aggressive behaviour,

              association with

              HTR1B

              C > T:TCC

               

              Chimpanzee

              CR073540

              Chr6

              131935252

              +

              DP

              Myocardial infarction,

              association with

              ARG1

              G > T:TTT

               

              Human

              CR052970

              Chr6

              132254387

              +

              DP

              Obesity, association

              with

              ENPP1

              A > G:GGG

               

              Human

              CR075243

              Chr6

              132314950

              -

              DFP

              Systemic sclerosis,

              association with

              CTGF

              C > G:CGG

               

              Ancient

              CR075274

              Chr6

              133077018

              -

              DP

              HDL cholesterol

              concentration,

              association with

              VNN1

              A > C:CCC

               

              Human

              CR077383

              Chr6

              154401054

              +

              FP

              Increased promoter

              activity, association

              with

              OPRM1

              A > G:GGG

               

              Human

              CR066667

              Chr7

              30969948

              +

              DP

              Breast cancer,

              decreased risk,

              association with

              GHRHR

              C > T:TTT

               

              Human

              CR092300

              Chr7

              111902894

              +

              DFP

              Severity in cystic

              fibrosis, association

              with

              IFRD1

              C > T:TTT

               

              Human

              CR068449

              Chr7

              128381961

              +

              DP

              SLE, association

              with?

              IRF5

              C > T:TTT

               

              Human

              CR022507

              Chr7

              136351848

              +

              DP

              Major depression in

              women, association

              with

              CHRM2

              T > A:AAA

               

              Human

              CR971950

              Chr8

              19840951

              +

              FP

              Lower plasma

              triglyceride level,

              association with

              LPL

              T > G:GGG

               

              Human

              CR023703

              Chr8

              120034205

              -

              DP

              Decreased bone

              mineral density,

              association with?

              TNFRSF11B

              C > T:TTT

               

              Human

              CR084001

              Chr9

              70877744

              +

              DP

              Myocardial infarction,

              association with

              FXN

              C > T:TTT

               

              Human

              CR102176

              Chr9

              100952292

              +

              DFP

              Breast cancer,

              association with

              TGFBR1

              A > G:GGG

               

              Human

              CR020827

              Chr9

              106730271

              -

              DP

              Increased risk of

              coronary artery

              disease, association

              with

              ABCA1

              G > A:AAA

               

              Human

              CR045560

              Chr9

              106730659

              -

              FP

              Reduced plasma

              HDL cholesterol,

              association with

              ABCA1

              C > G:GGG

               

              Human

              CR091269

              Chr9

              116608587

              -

              DFP

              Crohn's disease,

              susceptibility to,

              association with

              TNFSF15

              A > G:GGG

               

              Human

              CR034594

              Chr9

              124172343

              +

              FP

              Inhibition of

              prostaglandin H2

              formation,

              association with?

              PTGS1

              A > G:GAG

               

              Neanderthal

              and

              chimpanzee

              CR054255

              Chr9

              127043845

              -

              DP

              Bipolar disorder,

              association with?

              HSPA5

              T > C:CCC

               

              Human

              CR077381

              ChrX

              113724838

              +

              FP

              Reduced promoter

              activity, association

              with

              HTR2C

              G > C:CGG

               

              Chimpanzee

              CR063398

              ChrX

              135554616

              +

              FP

              Increased soluble

              CD40 ligand

              (CD40L) levels,

              association with

              CD40LG

              A > G:GGG

               

              Human

              Table S3

              PCMs covered by the Denisovan sequence but not the Neanderthal sequence

              Acc

              Chr

              Location

              Strand

              Tag

              Disease

              Gene

              Mutation

              AA seq

              Type

              CM062419

              chr1

              19483828

              -

              DP

              Leukaemia, risk,

              association with

              AKR7A3

              C > T:CT

              Asp-Asn

              Denisovan

              CM098300

              chr1

              24074507

              -

              DFP

              Eating disorders,

              association with

              CNR2

              T > C:CC

              Gln-Arg

              Ancestral

              CM066774

              chr1

              110267989

              +

              DP

              Periodontitis,

              association with?

              CSF1

              T > C:CC

              Leu-Pro

              Ancestral

              CM094244

              chr1

              111656412

              +

              FP

              Increased enzyme

              activity, association

              with?

              CHIA

              A > G:GA

              Asn-Asp

              Derived

              CM094243

              chr1

              111656461

              +

              DFP

              Asthma, protection

              against, association

              with?

              CHIA

              G > T:TG

              Arg-Met

              Derived

              CM084968

              chr1

              150552554

              -

              DP

              Psoriasis, increased

              risk, association with

              FLG

              G > A:AG

              Pro-Ser

              Derived

              CM067657

              chr1

              156591049

              +

              DP

              Guillain-Barré

              syndrome, reduced

              risk, association with

              CD1E

              A > G:GG

              Gln-Arg

              Ancestral

              CM033904

              chr1

              169444714

              +

              FP

              Flavin-containing

              monooxygenase 2

              (FMO2) gene variant

              FMO2

              T > C:CC

              Term-Gln

              Ancestral

              CM043273

              chr1

              195670491

              +

              DM

              Retinitis pigmentosa

              CRB1

              G > A:AG

              Gly-Ser

              Derived

              CM024366

              chr1

              224093029

              +

              DFP

              Preeclampsia,

              association with

              EPHX1

              A > G:GA

              His-Arg

              Derived

              CM994344

              chr10

              115795046

              +

              FP

              Gain of function,

              association with

              ADRB1

              G > C:CC

              Gly-Arg

              Ancestral

              CM067436

              chr11

              7020956

              +

              DM

              Spermatogenic

              failure

              NLRP14

              G > A:AG

              Ala-Thr

              Derived

              CM043536

              chr11

              47326617

              -

              DM

              Cardiomyopathy,

              hypertrophic?

              MYBPC3

              T > C:CT

              Ser-Gly

              Derived

              CM035848

              chr11

              57739196

              +

              FP

              Olfactory receptor

              deficiency?

              OR1S1

              G > A:GA

              Arg-His

              Denisovan

              CM087504

              chr11

              102218830

              -

              DP

              Blood pressure,

              association with

              MMP3

              T > C:CC

              Lys-Glu

              Ancestral

              CM041241

              chr11

              112776038

              +

              FP

              Reduced dopamine

              D2 receptor

              (DRD2) receptor

              density, association

              with?

              ANKK1

              G > A:AA

              Glu-Lys

              Ancestral

              CM082943

              chr11

              118720796

              -

              DM

              Primary

              angle-closure

              glaucoma?

              MFRP

              C > T:TT

              Arg-His

              Ancestral

              CM075018

              chr11

              130255852

              -

              DP

              Coronary heart

              disease, association

              with

              SNX19

              A > C:CC

              Leu-Arg

              Ancestral

              CM091988

              chr12

              32913201

              -

              DM

              Arrhythmogenic

              right ventricular

              cardiomyopathy

              PKP2

              A > G:GG

              Leu-Pro

              Ancestral

              CM087618

              chr12

              56152088

              +

              DFP

              Inflammatory bowel

              disease, association

              with

              GLI1

              G > C:CC

              Glu-Gln

              Ancestral

              CM098354

              chr12

              120099486

              +

              FP

              Altered function,

              association with

              P2RX7

              G > A:AA

              Ala-Thr

              Ancestral

              CM065186

              chr13

              38162690

              +

              DP

              Colorectal cancer,

              increased risk,

              association with

              FREM2

              T > C:CC

              Phe-Ser

              Ancestral

              CM063919

              chr13

              45546095

              -

              FP

              Higher

              thrombin-activatable

              fibrinolysis inhibitor

              (TAFI) antigen levels,

              association with

              CPB2

              C > T:TT

              Ala-Thr

              Ancestral

              CM044579

              chr13

              51413355

              -

              DM

              Wilson disease?

              ATP7B

              A > G:GG

              Val-Ala

              Ancestral

              CM063843

              chr14

              19994994

              +

              DFP

              Amyotrophic lateral

              sclerosis, association

              with

              APEX1

              T > G:GG

              Asp-Glu

              Ancestral

              CM073244

              chr14

              20010446

              +

              DP

              Faster cognitive

              decline in

              Alzheimer's disease,

              association with

              NP

              G > A:AG

              Gly-Ser

              Derived

              CM068495

              chr15

              49316404

              -

              DP

              Increased cortical

              bone mass density,

              association with

              CYP19A1

              T > C:CC

              Val-Val

              Ancestral

              CM045806

              chr15

              83248435

              +

              FP

              Reduced affinity for

              gemcitabine,

              association with

              SLC28A1

              G > A:AG

              Val-Ile

              Derived

              CM102885

              chr16

              10908349

              +

              DP

              Multiple sclerosis,

              increased risk,

              association with

              CIITA

              G > C:CC

              Gly-Ala

              Ancestral

              CM093131

              chr16

              55950234

              +

              DP

              Helicobacter

              pylori-related gastric

              carcinoma,

              association with

              CCL22

              A > C:CC

              Asp-Ala

              Ancestral

              CM067679

              chr17

              7858004

              +

              DP

              Lung cancer,

              susceptibility to,

              association with

              GUCY2D

              T > A:AA

              Leu-His

              Ancestral

              CM073339

              chr17

              24310977

              -

              DM

              Febrile seizures?

              SEZ6

              T > C:CC

              Thr-Ala

              Ancestral

              CM057951

              chr17

              37960432

              +

              DP

              Endometriosis,

              association with

              HSD17B1

              A > G:AG

              Ser-Gly

              Denisovan

              CM994214

              chr17

              39808591

              -

              DP

              Reduced post-stroke

              mortality, association

              with

              ITGA2B

              A > C:GC

              Ile-Ser

              Unsure

              CM091892

              chr17

              42363569

              +

              DP

              Hypertension,

              association with

              GOSR2

              G > A:AG

              Arg-Lys

              Derived

              CM091876

              chr17

              73642170

              +

              DP

              Epidermodysplasia

              verruciformis,

              susceptibility in HIV,

              association with

              TMC8

              A > T:TA

              Asn-Ile

              Derived

              CM000831

              chr19

              3546794

              -

              DP

              Bronchial asthma,

              association with

              TBXA2R

              A > G:GG

              Tyr-Tyr

              Ancestral

              CM030470

              chr19

              18041451

              -

              DP

              Tuberculosis,

              susceptibility to,

              association with

              IL12RB1

              A > G:GG

              Met-Thr

              Ancestral

              CM044082

              chr19

              18407678

              -

              DP

              Spina bifida, reduced

              risk, association with

              isyna1

              T > C:CC

              Leu-Leu

              Ancestral

              CM057586

              chr19

              40534926

              +

              DP

              Increased beta-cell

              function, association

              with

              FFAR1

              G > A:AA

              Arg-His

              Ancestral

              CM057545

              chr19

              50560149

              -

              DP

              Lung adenocarcinoma,

              increased risk,

              association with

              ERCC2

              G > T:GT

              Arg-Arg

              Denisovan

              CM044227

              chr19

              60088712

              +

              DP

              Aggressive

              periodontitis,

              reduced risk, assoc

              with

              FCAR

              A > G:GG

              Arg-Arg

              Ancestral

              CM003809

              chr2

              38155681

              -

              DP

              Breast or lung

              cancer, association

              with

              CYP1B1

              C > A:AA

              Ala-Ser

              Ancestral

              CM101950

              chr2

              98363138

              +

              DM

              Progressive cone

              dystrophy?

              CNGA3

              C > T:TC

              Pro-Leu

              Derived

              CM092797

              chr2

              169550992

              -

              FP

              Alternate splicing,

              association with

              ABCB11

              T > C:CT

              Gly-Gly

              Derived

              CM066575

              chr2

              218738088

              -

              DP

              AIDS progression,

              protection,

              association with

              IL8RA

              A > C:CC

              Met-Arg

              Ancestral

              CM057769

              chr2

              234266408

              +

              FP

              Altered enzyme

              activity, association

              with

              UGT1A6

              T > G:GG

              Ser-Ala

              Ancestral

              CM910018

              chr2

              241466189

              +

              DP

              Hyperoxaluria,

              association with

              AGXT

              A > G:GG

              Ile-Met

              Ancestral

              CM053304

              chr20

              54257212

              +

              DP

              Obesity, association

              with

              MC3R

              C > A:AA

              Thr-Lys

              Ancestral

              CM970391

              chr22

              18331207

              +

              DFP

              Schizoaffective

              disorder, association

              with

              COMT

              C > G:GG

              Leu-Leu

              Ancestral

              CM961335

              chr22

              30817700

              +

              DM

              Glucose/galactose

              malabsorption

              SLC5A1

              G > A:AA

              Ala-Thr

              Ancestral

              CM930187

              chr22

              40853887

              -

              DP

              Parkinson's disease,

              association with

              CYP2D6

              G > A:GA

              Arg-Cys

              Denisovan

              CM099899

              chr22

              41888870

              +

              FP

              Increased

              pregnenolone levels,

              association with

              TSPO

              A > G:GG

              Thr-Ala

              Ancestral

              CM025430

              chr4

              2975841

              +

              FP

              Activity, association

              with

              GRK4

              C > T:TT

              Ala-Val

              Ancestral

              CM013959

              chr4

              23424760

              -

              DP

              Diabetes, type 2,

              association with

              PPARGC1A

              C > T:TC

              Gly-Ser

              Derived

              CM033593

              chr4

              100479812

              -

              DP

              Alcoholism,

              increased risk,

              association with?

              ADH1C

              T > C:CC

              Ile-Val

              Ancestral

              CM064956

              chr4

              109893565

              -

              DP

              Colorectal cancer,

              increased risk,

              association with

              AGXT2L1

              A > G:GG

              Ser-Pro

              Ancestral

              CM030066

              chr4

              149576925

              -

              FP

              Reduced expression,

              association with

              NR3C2

              T > C:TC

              Ile-Val

              Denisovan

              CM080365

              chr4

              155711209

              +

              DP

              Increased clot

              stiffness, association

              with

              FGB

              G > A:AA

              Arg-Lys

              Ancestral

              CM057405

              chr4

              156355126

              +

              DP

              Severe obesity, in

              men, association

              with

              NPY2R

              C > T:TT

              Ile-Ile

              Ancestral

              CM067358

              chr5

              22114341

              -

              DP

              Lung cancer,

              susceptibility to,

              association with

              CDH12

              C > T:TT

              Val-Met

              Ancestral

              CM094788

              chr5

              121441107

              -

              DFP

              Breast cancer,

              increased risk, in

              African American

              women, association

              with

              LOX

              C > T:TT

              Arg-Gln

              Ancestral

              CM013815

              chr5

              147461148

              +

              DP

              Atopy, maternally

              inherited,

              association with

              SPINK5

              G > A:GA

              Glu-Lys

              Denisovan

              CM083577

              chr6

              24611569

              +

              DFP

              Impaired cognitive

              function, association

              with

              ALDH5A1

              C > T:TT

              His-Tyr

              Ancestral

              CM086146

              chr6

              25921129

              -

              DP

              Uric acid

              concentration,

              association with

              SLC17A1

              G > A:AA

              Thr-Ile

              Ancestral

              CM052232

              chr6

              80683094

              -

              DP

              Age-related

              maculopathy,

              association with

              ELOVL4

              T > C:CT

              Met-Val

              Derived

              CM073245

              chr7

              34784638

              +

              DP

              Panic disorder, in

              males, association

              with

              NPSR1

              A > T:TT

              Asn-Ile

              Ancestral

              CM084696

              chr7

              87017537

              -

              DFP

              Parkinson's disease,

              association with

              ABCB1

              A > G:GG

              Gly-Gly

              Ancestral

              CM091200

              chr7

              129737976

              +

              DP

              Prostate cancer,

              aggressive

              early-onset,

              association with

              CPA4

              G > T:TT

              Gly-Cys

              Ancestral

              CM952203

              chr7

              142350235

              -

              FP

              Kell blood group

              variation

              KEL

              A > G:GA

              Leu-Pro

              Derived

              CM073993

              chr7

              150188598

              +

              FP

              Reduced activity,

              association with

              ABP1

              C > G:GG

              His-Asp

              Ancestral

              CM973386

              chr8

              18124281

              +

              FP

              Increased activity,

              association with

              NAT1

              G > A:AG

              Val-Ile

              Derived

              CM099895

              chr8

              24412708

              +

              DP

              Schizophrenia,

              association with

              ADAM7

              A > C:CC

              Asn-His

              Ancestral

              CM064954

              chr8

              26683945

              -

              DP

              Hypertension,

              association with?

              ADRA1A

              A > G:GG

              Cys-Arg

              Ancestral

              CM033767

              chr8

              27414422

              +

              DFP

              Coronary heart

              disease, in

              Caucasians,

              association with

              EPHX2

              A > G:GA

              Lys-Arg

              Derived

              CM034886

              chr8

              91059655

              -

              DP

              Lung cancer,

              association with?

              NBN

              C > G:GG

              Glu-Gln

              Ancestral

              CM045665

              chr8

              120033233

              -

              DP

              Osteoporotic

              fractures, association

              with

              TNFRSF11B

              G > C:CG

              Asn-Lys

              Derived

              CM093465

              chr9

              2181309

              +

              DFP

              Schizophrenia,

              association with

              SMARCA2

              C > G:GC

              Asp-Glu

              Derived

              CM073190

              chrX

              43475980

              +

              DP

              Bipolar disorder,

              association with?

              MAOA

              T > G:TG

              Arg-Arg

              Denisovan

              CR072321

              chr1

              11841858

              -

              DFP

              Diabetes, type, 2,

              reduced risk,

              association with

              NPPB

              A > G:GG

               

              Ancestral

              CR080762

              chr1

              15645754

              +

              DM

              Pancreatitis, chronic?

              CTRC

              T > C:CC

               

              Ancestral

              CR080761

              chr1

              15645757

              +

              DM

              Pancreatitis, chronic?

              CTRC

              A > G:GG

               

              Ancestral

              CR016187

              chr1

              87101113

              -

              FP

              Increased

              selenocysteine

              insertion sequence

              (SECIS) efficiency,

              association with

              sep15

              C > T:TT

               

              Ancestral

              CR092707

              chr1

              201194130

              -

              DFP

              Lower insulin

              resistance,

              association with

              ADIPOR1

              C > T:TT

               

              Ancestral

              CR034628

              chr10

              26545502

              +

              DP

              Obesity, association

              with?

              GAD2

              G > A:GA

               

              Denisovan

              CR061340

              chr11

              35397552

              -

              DFP

              Progressing stroke,

              increased risk,

              association with

              SLC1A2

              T > G:GG

               

              Ancestral

              CR068212

              chr11

              59612604

              +

              DFP

              Asthma,

              aspirin-intolerant

              MS4A2

              T > C:CC

               

              Ancestral

              CR063407

              chr14

              50069895

              -

              DP

              Diabetes, type 2,

              reduced risk,

              association with

              MAP4K5

              G > A:AA

               

              Ancestral

              CR077666

              chr15

              71712835

              -

              DFP

              Schizophrenia,

              reduced risk,

              association with?

              NPTN

              C > A:CA

               

              Denisovan

              CR084880

              chr17

              35697157

              +

              DFP

              Hepatocellular

              carcinoma, reduced

              risk, association with

              CDC6

              A > G:GG

               

              Ancestral

              CR087465

              chr17

              39785770

              +

              DFP

              Frontotemporal

              dementia,

              association with

              GRN

              C > T:TT

               

              Ancestral

              CR035036

              chr18

              647685

              +

              FP

              Transcriptional

              activity, association

              with

              TYMS

              G > C:CC

               

              Ancestral

              CR032436

              chr18

              45342041

              +

              DP

              High-density

              lipoprotein (HDL)

              cholesterol levels,

              association with?

              LIPG

              A > C:CA

               

              Derived

              CR087182

              chr19

              44589133

              +

              DFP

              Rheumatoid

              arthritis, shorter

              duration, association

              with

              ZFP36

              A > G:GG

               

              Ancestral

              CR035033

              chr19

              46188301

              +

              FP

              Cytochrome P-450

              (CYP) 2B6

              expression,

              association with?

              CYP2B6

              T > C:CC

               

              Ancestral

              CR068525

              chr2

              69467665

              -

              DFP

              Diabetes, type 2,

              association with

              GFPT1

              A > G:GG

               

              Ancestral

              CR077669

              chr2

              85748849

              -

              FP

              Increased promoter

              activity, association

              with

              SFTPB

              T > G:GG

               

              Ancestral

              CR093507

              chr2

              168743982

              -

              DFP

              Hypertension,

              association with

              STK39

              A > G:GG

               

              Ancestral

              CR093026

              chr2

              169465787

              +

              DFP

              Increased insulin

              secretion,

              association with

              G6PC2

              G > A:AA

               

              Ancestral

              CR073559

              chr2

              224174588

              -

              DFP

              Hypertension,

              association with

              SCG2

              C > T:TT

               

              Ancestral

              CR053505

              chr20

              4653756

              +

              DP

              Creutzfeldt-Jakob

              disease, association

              with?

              PRND

              T > C:CC

               

              Ancestral

              CR015272

              chr22

              40858326

              -

              FP

              Intermediate

              metaboliser,

              association with?

              CYP2D6

              C > G:GG

               

              Ancestral

              CR055620

              chr4

              75938792

              -

              FP

              Promoter activity,

              association with

              BTC

              C > G:GG

               

              Ancestral

              CR093469

              chr6

              2945302

              +

              DFP

              Breast cancer,

              decreased risk,

              association with

              NQO2

              A > C:CA

               

              Derived

              CR035882

              chr6

              78230101

              -

              DFP

              Suicidal ideation, in

              major depression,

              association with

              HTR1B

              A > C:CA

               

              Derived

              CR025333

              chr6

              137582213

              -

              DFP

              Malaria,

              susceptibility,

              association with

              IFNGR1

              A > G:GG

               

              Ancestral

              CR093919

              chr6

              153121754

              +

              DP

              Pulmonary arterial

              hypertension,

              idiopathic,

              association with?

              VIP

              T > C:CC

               

              Ancestral

              CR016149

              chr7

              22732746

              +

              FP

              Altered

              transcriptional

              activity, association

              with

              IL6

              A > G:GG

               

              Ancestral

              CR053504

              chr7

              91995822

              -

              FP

              Gene expression,

              association with

              PEX1

              A > G:GA

               

              Derived

              CR041138

              chr7

              99192235

              -

              DP

              Prostate cancer, low

              aggressiveness,

              association with

              CYP3A4

              G > A:AG

               

              Derived

              CR072316

              chr7

              128376663

              +

              FP

              Shorter transcript,

              association with

              IRF5

              G > A:AA

               

              Ancestral

              CR962526

              chr8

              41774321

              -

              DM

              Spherocytosis

              ANK1

              A > G:GA

               

              Derived

              CR098013

              chr9

              22109195

              +

              DFP

              Coronary artery

              disease, association

              with

              CDKN2BAS

              C > T:CT

               

              Denisovan

              CR044772

              chr9

              99499399

              -

              DP

              Lung adenocarcinoma,

              risk, association with

              XPA

              T > C:CC

               

              Ancestral

              CR020828

              chr9

              106730356

              -

              DP

              Reduced risk of

              coronary artery

              disease, association

              with

              ABCA1

              G > C:CC

               

              Ancestral

              CR052068

              chr9

              136911887

              +

              FP

              Promoter activity,

              association with

              FCN2

              A > G:GG

               

              Ancestral

              CR042847

              chr9

              138995962

              +

              DP

              HDL cholesterol,

              association with?

              PTGDS

              A > C:CC

               

              Ancestral

              Human variants with significantly different population frequencies at sites of PCMs

              The FST was used to quantify the allele frequency differences for the different polymorphic PCMs between extant African, Asian and European populations. Alleles that have been the target of localised positive selection tend to exhibit unusually high FST values [22, 23]. We therefore compared the FST values of the ancestral polymorphic PCMs with the empirical FST distribution derived from all HapMap SNPs (International HapMap Consortium, 2007),[24] to assess the significance of individual FST values. We identified six PCMs with significantly elevated FST values (Table 5).
              Table 5

              PCMs (disease-causing and disease-related) with significantly different genotype frequencies in different HapMap populations

                   

              Asian

              European

              African

              Pair-wise FST (pvalue)

              Gene

              rs

              HGMD

              Acc

              WT

              PCM

              fWT

              n

              fWT

              n

              fWT

              n

              Asian-African

              European-African

              Asian-European

              SLC24A5

              rs1426654

              CM054862

              A

              G

              0.01

              178

              1.00

              116

              0.03

              120

              -0.001 (0.8490)

              0.974 (0.0054)

              0.987 (0.0010)

              TP53BP1*

              rs2602141

              CM067476

              T

              G

              0.52

              176

              0.69

              120

              0.00

              120

              0.470 (0.2830)

              0.689 (0.0489)

              0.054 (0.5701)

              CAPN3*

              rs1801449

              CM099258

              G

              A

              0.91

              178

              0.94

              120

              0.23

              120

              0.653 (0.2234)

              0.143 (0.3877)

              0.680 (0.0026)

              TP53BP1*

              rs560191

              CM067475

              G

              C

              0.52

              178

              0.69

              120

              0.00

              120

              0.475 (0.2981)

              0.689 (0.0489)

              0.051 (0.5536)

              ADH1B

              rs1229984

              CM890003

              T

              C

              0.75

              178

              0.00

              120

              0.00

              118

              0.715 (0.1576)

              NA (NA)

              0.717 (0.0197)

              ENPP1*

              rs1044498

              CM993455

              A

              C

              0.94

              180

              0.87

              118

              0.00

              120

              0.927 (0.0314)

              0.873 (0.0110)

              0.020 (0.6004)

              *Previously reported by Zhang et al.[10]

              rs: reference number, dbSNP, WT: wild type, fWT: frequency of the wild-type allele, NA: Not applicable.

              Although four of these PCMs had already been identified in our previous comparative analysis of the human, chimpanzee and Neanderthal genomes,[10] two novel PCMs were identified in the putative cation exchanger SLC24A5 (DP) gene and in the alcohol dehydrogenase ADH1B (FP) gene. These genes have in common the GO terms GO:0046872, GO:0043169 and GO:0043167, terms which relate to metal ion binding, cation binding and ion binding, respectively. The SLC24A5 variant appears to be associated with increased skin pigmentation and predominates in African/East Asian populations [25, 26].

              In conclusion, using the newly reported genome sequence from a Denisovan hominin, we have identified a number of PCMs in the chimpanzee, Neanderthal and Denisovan. Those human PCMs that were ancestral (ie both the Denisovan nucleotide and the chimpanzee nucleotide were identical to the human DM/disease-associated mutation) could potentially be indicative of either the human lineage-specific loss of compensatory nucleotide changes within the respective genes carrying the PCM, or adaptive differences between modern humans and Denisovans.

              Authors’ Affiliations

              (1)
              Bioinformatics Department, Beijing Genomics Institute at Shenzhen
              (2)
              Institute of Medical Genetics, School of Medicine, Cardiff University
              (3)
              Institute of Human Genetics, University of Ulm

              References

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              4. Reich D, Green RE, Kircher M, Krause J, et al: Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature. 2010, 468: 1053-1060. 10.1038/nature09710.PubMed CentralView ArticlePubMed
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