Open Access

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

  • Guojie Zhang1Email author,
  • Zhang Pei1,
  • Edward V Ball2,
  • Matthew Mort2,
  • Hildegard Kehrer-Sawatzki3 and
  • David N Cooper2
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

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Copyright

© Henry Stewart Publications 2011

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