Human mtDNA subject to selection by climate?

Climate shaped the worldwide distribution of human mitochondrial DNA sequence variation
François Balloux, Lori-Jayne Lawson Handley, Thibaut Jombart, Hua Liu and Andrea Manica
Proceedings Royal Society B

Abstract: There is an ongoing discussion in the literature on whether human mitochondrial DNA (mtDNA) evolves neutrally. There have been previous claims for natural selection on human mtDNA based on an excess of non-synonymous mutations and higher evolutionary persistence of specific mitochondrial mutations in Arctic populations. However, these findings were not supported by the reanalysis of larger datasets. Using a geographical framework, we perform the first direct test of the relative extent to which climate and past demography have shaped the current spatial distribution of mtDNA sequences worldwide. We show that populations living in colder environments have lower mitochondrial diversity and that the genetic differentiation between pairs of populations correlates with difference in temperature. These associations were unique to mtDNA; we could not find a similar pattern in any other genetic marker. We were able to identify two correlated non-synonymous point mutations in the ND3 and ATP6 genes characterized by a clear association with temperature, which appear to be plausible targets of natural selection producing the association with climate. The same mutations have been previously shown to be associated with variation in mitochondrial pH and calcium dynamics. Our results indicate that natural selection mediated by climate has contributed to shape the current distribution of mtDNA sequences in humans.

Social brain hypothesis shot down twice in two days?!

Why do some animals have bigger brains? There's several hypotheses out there, including the monogamy one which was tested in the first paper below, but the strongest one, in my mind, the social complexity (or Machiavellian intelligence) hypothesis, has been "shot down" twice in recent papers. These hypotheses are not necessarily mutually exclusive, and the ecological determinants of brain size are likely to differ by taxa/clade/lineage.

Sociality, ecology, and relative brain size in lemurs
Evan L. MacLean, Nancy L. Barrickman, Eric M. Johnson and Christine E. Wall
Journal of Human Evolution Volume 56, Issue 5, May 2009, Pages 471-478

Abstract: The social brain hypothesis proposes that haplorhine primates have evolved relatively large brains for their body size primarily as an adaptation for living in complex social groups. Studies that support this hypothesis have shown a strong relationship between relative brain size and group size in these taxa. Recent reports suggest that this pattern is unique to haplorhine primates; many nonprimate taxa do not show a relationship between group size and relative brain size. Rather, pairbonded social monogamy appears to be a better predictor of a large relative brain size in many nonprimate taxa. It has been suggested that haplorhine primates may have expanded the pairbonded relationship beyond simple dyads towards the evolution of complex social groups. We examined the relationship between group size, pairbonding, and relative brain size in a sample of 19 lemurs; strepsirrhine primates that last share a common ancestor with monkeys and apes approximately 75 Ma. First, we evaluated the social brain hypothesis, which predicts that species with larger social groups will have relatively larger brains. Secondly, we tested the pairbonded hypothesis, which predicts that species with a pairbonded social organization will have relatively larger brains than non-pairbonded species. We found no relationship between group size or pairbonding and relative brain size in lemurs. We conducted two further analyses to test for possible relationships between two nonsocial variables, activity pattern and diet, and relative brain size. Both diet and activity pattern are significantly associated with relative brain size in our sample. Specifically, frugivorous species have relatively larger brains than folivorous species, and cathemeral species have relatively larger brains than diurnal, but not nocturnal species. These findings highlight meaningful differences between Malagasy strepsirrhines and haplorhines, and between Malagasy strepsirrhines and nonprimate taxa, regarding the social and ecological factors associated with increases in relative brain size. The results suggest that factors such as foraging complexity and flexibility of activity patterns may have driven selection for increases in brain size in lemurs.

Brain-size evolution and sociality in Carnivora
John A. Finarelli, John J. Flynn
PNAS June 9, 2009 vol. 106 no. 23 9345-9349

Abstract: Increased encephalization, or larger brain volume relative to body mass, is a repeated theme in vertebrate evolution. Here we present an extensive sampling of relative brain sizes in fossil and extant taxa in the mammalian order Carnivora (cats, dogs, bears, weasels, and their relatives). By using Akaike Information Criterion model selection and endocranial volume and body mass data for 289 species (including 125 fossil taxa), we document clade-specific evolutionary transformations in encephalization allometries. These evolutionary transformations include multiple independent encephalization increases and decreases in addition to a remarkably static basal Carnivora allometry that characterizes much of the suborder Feliformia and some taxa in the suborder Caniformia across much of their evolutionary history, emphasizing that complex processes shaped the modern distribution of encephalization across Carnivora. This analysis also permits critical evaluation of the social brain hypothesis (SBH), which predicts a close association between sociality and increased encephalization. Previous analyses based on living species alone appeared to support the SBH with respect to Carnivora, but those results are entirely dependent on data from modern Canidae (dogs). Incorporation of fossil data further reveals that no association exists between sociality and encephalization across Carnivora and that support for sociality as a causal agent of encephalization increase disappears for this clade.

Hygiene hypothesis: exposure to parasites and autoimmune diseases

They use re-sequencing data on interleukin genes retrieved from Seattle SNPs.

Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions
Matteo Fumagalli, Uberto Pozzoli, Rachele Cagliani, Giacomo P. Comi, Stefania Riva, Mario Clerici, Nereo Bresolin, and Manuela Sironi
The Journal of Experimental Medicine doi:10.1084/jem.20082779

Abstract: Many human genes have adapted to the constant threat of exposure to infectious agents; according to the "hygiene hypothesis," lack of exposure to parasites in modern settings results in immune imbalances, augmenting susceptibility to the development of autoimmune and allergic conditions. Here, by estimating the number of pathogen species/genera in a specific geographic location (pathogen richness) for 52 human populations and analyzing 91 interleukin (IL)/IL receptor genes (IL genes), we show that helminths have been a major selective force on a subset of these genes. A population genetics analysis revealed that five IL genes, including IL7R and IL18RAP, have been a target of balancing selection, a selection process that maintains genetic variability within a population. Previous identification of polymorphisms in some of these loci, and their association with autoimmune conditions, prompted us to investigate the relationship between adaptation and disease. By searching for variants in IL genes identified in genome-wide association studies, we verified that six risk alleles for inflammatory bowel (IBD) or celiac disease are significantly correlated with micropathogen richness. These data support the hygiene hypothesis for IBD and provide a large set of putative targets for susceptibility to helminth infections.

GWAS and fine mapping in Africans

Genome-wide and fine-resolution association analysis of malaria in West Africa.
Jallow M, Teo YY, Small KS et al.
Nat Genet. 2009 May 24. [Epub ahead of print]

Abstract: We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 x 10(-7) to P = 4 x 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

Geography and genetics of p53 in E. Asia

Winter Temperature and UV Are Tightly Linked to Genetic Changes in the p53 Tumor Suppressor Pathway in Eastern Asia
Hong Shi,Si-jie Tan,Hua Zhong,Wenwei Hu,Arnold Levine,Chun-jie Xiao,Yi Peng,Xue-bin Qi,Wei-hua Shou,Run-lin Z. Ma,Yi Li,Bing Su, andXin Lu
AJHG Volume 84, Issue 4, 534-541, 02 April 2009

Abstract: The tumor suppressor p53 is a master sensor of stress. Two human-specific polymorphisms, p53 codon 72 and MDM2 SNP309, influence the activities of p53. There is a tight association between cold winter temperature and p53 Arg72 and between low UV intensity and MDM2 SNP309 G/G in a cohort of 4029 individuals across Eastern Asia that suggests causative selection. Moreover, the two polymorphisms are not coselected. Haplotype-based selection analysis further suggests that this is a striking example of two functional polymorphisms being strongly selected for in human populations in response to environmental stresses.

GWAS articles in NEJM

Razib's got the links.

Lumberjacks and obesity genes

Thought I'd post on this one, because the title caught my eye, and because I was keen on finding a good lumberjack picture. They look for association between variants in 18 genes and obesity related phenotypes. I'm a bit perplexed by the choice of genes...

Association study between candidate genes and obesity-related phenotypes using a sample of lumberjacks.

Chamberland A, Tremblay N, Audet M, Gilbert B, Pérusse L, Vohl MC, Laprise C.

Public Health Genomics. 2009;12(4):253-8. Epub 2009 Feb 16.

INTRODUCTION: Complex traits such as obesity are modulated by genetic and environmental factors and lead to varied clinical presentations.The aim of this study was to investigate associations between candidate genes and obesity-related phenotypes using a sample of 252 lumberjacks issued from a founder population and sharing a common and circumscribed environment. METHODS: Thirty-seven variants in 18 genes were genotyped. The restriction fragment length polymorphism method and the template-directed dye-terminator incorporation assay with fluorescence polarization detection were employed for the genotyping assays. Multivariate logistic regression models were built in order to calculate the relative odds of exhibiting obesity-related phenotypes associated with the presence of the studied polymorphism. Among them, 21 single nucleotide polymorphisms were tested for associations with obesity phenotypes. RESULTS: Significant associations were found between carriers of the minor alleles of APOE-epsilon2, FABP2-A54T, UCP1-L229M, LPL-HindIII, LPL-S447X and LPL-T1973C, patients bearing a combination of LPL-D9N, LPL-N291S and LPL-P207L and obesity-related phenotypes. CONCLUSION: The present results suggest that a particular population such as lumberjacks, sharing the same environment, could help target genes involved in complex traits.

Answer to my question (sorta): heritability of melanoma

I wondered about the heritability of tanning response in a recent post about a GWAS for tanning response. Albeit not a direct answer, according to this paper below, there is a relatively high degree of heritability (~55%) for variation in development of melanoma:

A Population-Based Study of Australian Twins with Melanoma Suggests a Strong Genetic Contribution to Liability.
Shekar SN, Duffy DL, Youl P, Baxter AJ, Kvaskoff M, Whiteman DC, Green AC, Hughes MC, Hayward NK, Coates M, Martin NG.
J Invest Dermatol. 2009 Apr 9.

Abstract: Melanoma runs within families, but this may be due to either shared genetic or shared environmental influences within those families. The concordance between pairs of non-identical twins compared to that between identical twins can be used to determine whether familial aggregation is due to genetic or environmental factors. Mandatory reporting of melanoma cases in the state of Queensland yielded approximately 12,000 cases between 1982 and 1990. Twins in this study and from the adjacent state of New South Wales (125 pairs in total) were used to partition variation in liability to melanoma into genetic and environmental factors. Identical twins were more concordant for melanoma (4 of 27 pairs) than non-identical twins (3 of 98 pairs; P-value approximately 0.04). Identical co-twins of affected individuals were 9.8 times more likely to be affected than by chance. However, non-identical co-twins of affected individuals were only 1.8 times more likely to be affected than by chance. An MZ:DZ recurrence risk ratio of 5.6 suggests that some of the genetic influences on melanoma are due to epistatic (gene-gene) interactions. Using these data and population prevalences, it was estimated that 55% of the variation in liability to melanoma is due to genetic influences.

Evolutionary medicine gaining ground

Description of Evolutionary Medicine meeting in the current Science:
Apparently there is a growing trend of teaching medicine from an evolutionary perspective in medical schools. The figure here shows the increase in connections between ecology & evolution and Medicine as reflected in citations (look at connections between the two reddish dots).
Some interesting parts from Elizabeth Pennisi's article:

For instance, anthropologist Kathleen Barnes of Johns Hopkins University has evidence that for some asthmatics, this overly energetic inflammatory response may be a holdover from the body's successes in coping with parasitic disease.

...With genomic data in hand, "medical students are much more equipped to understand the connections between all organisms,"...

Barnes and her colleagues have found that asthma is associated with the defective Duffy gene in populations in Brazil, Columbia, and the Caribbean whose recent African ancestors lived where malaria was endemic.

Also, in this issue, from the same meeting, a piece about schizophrenia and autism by Constance Holden, arguing for the evolutionary connection between these two conditions (I think that an equally appropriate spectrum is: William's syndrome-Autism)

At the Sackler Colloquium on Evolution in Health and Medicine held last week at the National Academy of Sciences (NAS) in Washington, D.C., evolutionary geneticist Bernard Crespi of Simon Fraser University in Burnaby, Canada, threw some evolutionary firepower at the question. He proposes that both schizophrenia and autism are disorders of the "social brain"--but at opposite ends of the same spectrum.

A number of studies have shown some overlap in genomic "hot spots" for CNVs in schizophrenia and autism, with, in some cases, deletions in one condition just where there are duplications for the other

That would fit with their theory that psychotic disorders--including not only schizophrenia but also bipolar disorder and some major depression--result from "overdevelopment" of the social brain, and autism spectrum disorders reflect underdevelopment of that brain. Many scientists believe socialization is the main force behind the rapid expansion of human brains, said Crespi, pointing out that in primates the size of the cortex increases with size of social groups. The components of the social brain, according to Crespi, include language, self-awareness, "social emotions" such as pride and guilt, logical thinking, pursuit of goals, and awareness of the mental states of others.

Utility of GWAS prostate cancer risk alleles in other populations

Generalizability of Associations from Prostate Cancer Genome-Wide Association Studies in Multiple Populations.
Waters KM, Le Marchand L, Kolonel LN, Monroe KR, Stram DO, Henderson BE, Haiman CA.
Cancer Epidemiol Biomarkers Prev. 2009 Mar 24. [Epub ahead of print]

Abstract: Genome-wide association studies have identified multiple common alleles associated with prostate cancer risk in populations of European ancestry. Testing these variants in other populations is needed to assess the generalizability of the associations and may guide fine-mapping efforts. We examined 13 of these risk variants in a multiethnic sample of 2,768 incident prostate cancer cases and 2,359 controls from the Multiethnic Cohort (African Americans, European Americans, Latinos, Japanese Americans, and Native Hawaiians). We estimated ethnic-specific and pooled odds ratios and tested for ethnic heterogeneity of effects using logistic regression. In ethnic-pooled analyses, 12 of the 13 variants were positively associated with risk, with statistically significant associations (P less than 0.05) noted with six variants: JAZF1, rs10486567 [odds ratio (OR), 1.23; 95% confidence interval (95% CI, 1.12-1.35); Xp11.2, rs5945572 (OR, 1.31; 95% CI, 1.13-1.51); HNF1B, rs4430796 (OR, 1.15; 95% CI, 1.06-1.25); MSMB, rs10993994 (OR, 1.13; 95% CI, 1.04-1.23); 11q13.2, rs7931342 (OR, 1.13; 95% CI, 1.03-1.23); 3p12.1, rs2660753 (OR, 1.11; 95% CI, 1.01-1.21); SLC22A3, rs9364554 (OR, 1.10; 95% CI, 1.00-1.21); CTBP2, rs12769019 (OR, 1.11; 95% CI, 0.99-1.25); HNF1B, rs11649743 (OR, 1.10; 95% CI, 0.99-1.22); EHBP1, rs721048 (OR, 1.08; 95% CI, 0.94-1.25); KLK2/3, rs2735839 (OR, 1.06; 95% CI, 0.97-1.16); 17q24.3, rs1859962 (OR, 1.04; 95% CI, 0.96-1.13); and LMTK2, rs6465657 (OR, 0.99; 95% CI, 0.89-1.09). Significant ethnic heterogeneity of effects was noted for four variants (EHBP1, Phet = 3.9 x 10(-3); 11q13, Phet = 0.023; HNF1B (rs4430796), Phet = 0.026; and KLK2/3, Phet = 2.0 x 10(-3)). Although power was limited in some ethnic/racial groups due to variation in sample size and allele frequencies, these findings suggest that a large fraction of prostate cancer variants identified in populations of European ancestry are global markers of risk. For many of these regions, fine-mapping in non-European samples may help localize causal alleles and better determine their contribution to prostate cancer risk in the population.

GWAS deluge

I wonder how exactly they operationalize this phenotype...I don't have full text access, but I'll assume they control for constitutive skin color. I still think this is a bit weird. Is there a heritable component to skin burning that is really independent of constitutive skin color?

Genome-Wide Association Study of Tanning Phenotype in a Population of European Ancestry.
Nan H, Kraft P, Qureshi AA, Guo Q, Chen C, Hankinson SE, Hu FB, Thomas G, Hoover RN, Chanock S, Hunter DJ, Han J.
J Invest Dermatol. 2009 Apr 2

Abstract: We conducted a multistage genome-wide association study (GWAS) of tanning response after exposure to sunlight in over 9,000 men and women of European ancestry who live in the United States. An initial analysis of 528,173 single-nucleotide polymorphisms (SNPs) genotyped on 2,287 women identified LOC401937 (rs966321) on chromosome 1 as a novel locus highly associated with tanning ability, and we confirmed this association in 870 women controls from a skin cancer case-control study with joint P-value=1.6 x 10(-9). We further genotyped this SNP in two subsequent replication studies (one with 3,750 women and the other with 2,405 men). This association was not replicated in either of these two studies. We found that several SNPs reaching the genome-wide significance level are located in or adjacent to the loci previously known as pigmentation genes: MATP, IRF4, TYR, OCA2, and MC1R. Overall, these tanning ability-related loci are similar to the hair color-related loci previously reported in the GWAS of hair color.

Blue eyes follow-up

According to this paper, blue eyes in N. European humans is predicted very well by these variants:
HERC2 rs12913832
OCA2 rs1800407
SLC24A4 rs12896399
SLC45A2 rs16891982
TYR rs1393350
IRF4 rs12203592

It might be interesting to look at the five latter ones in the blue-eyed lemur... although, it looks like only one SNP (in HERC2, I assume) is sufficient to explain the majority of the variation in humans.

Convergent evolution via different genetic mechanism: blue eyes in lemurs and humans

I guess we are to assume that the blue eye color is the same in humans and lemurs. From looking at some pictures, the color appears pretty similar. Haven't read the paper, but are all cases of blue eye color in humans explained by the same variation in HERC2? I might have a post on this somewhere.
I suppose we shouldn't be too surprised by this finding, given what we know about convergence of light skin color evolution in Europeans and E. Asians via different genes.

Brief communication: Blue eyes in lemurs and humans: Same phenotype, different genetic mechanism.
Bradley BJ, Pedersen A, Mundy NI.
Am J Phys Anthropol. 2009 Mar 10.

Almost all mammals have brown or darkly-pigmented eyes (irises), but among primates, there are some prominent blue-eyed exceptions. The blue eyes of some humans and lemurs are a striking example of convergent evolution of a rare phenotype on distant branches of the primate tree. Recent work on humans indicates that blue eye color is associated with, and likely caused by, a single nucleotide polymorphism (rs12913832) in an intron of the gene HERC2, which likely regulates expression of the neighboring pigmentation gene OCA2. This raises the immediate question of whether blue eyes in lemurs might have a similar genetic basis. We addressed this by sequencing the homologous genetic region in the blue-eyed black lemur (Eulemur macaco flavifrons; N = 4) and the closely-related black lemur (Eulemur macaco macaco; N = 4), which has brown eyes. We then compared a 166-bp segment corresponding to and flanking the human eye-color-associated region in these lemurs, as well as other primates (human, chimpanzee, orangutan, macaque, ring-tailed lemur, mouse lemur). Aligned sequences indicated that this region is strongly conserved in both Eulemur macaco subspecies as well as the other primates (except blue-eyed humans). Therefore, it is unlikely that this regulatory segment plays a major role in eye color differences among lemurs as it does in humans. Although convergent phenotypes can sometimes come about via the same or similar genetic changes occurring independently, this does not seem to be the case here, as we have shown that the genetic basis of blue eyes in lemurs differs from that of humans.

Disentangling genetic signatures of natural selection and demography among Native Americans and W. Beringians

Haplotypic background of a private allele at high frequency in the Americas.
Schroeder KB, Jakobsson M, Crawford MH, Schurr TG, Boca SM, Conrad DF, Tito RY, Osipova LP, Tarskaia LA, Zhadanov SI, Wall JD, Pritchard JK, Malhi RS, Smith DG, Rosenberg NA.
Mol Biol Evol. 2009 Feb 17. [Epub ahead of print]

Abstract: Recently, the observation of a high-frequency private allele, the 9-repeat allele at microsatellite D9S1120, in all sampled Native American and Western Beringian populations has been interpreted as evidence that all modern Native Americans descend primarily from a single founding population. However, this inference assumed that all copies of the 9-repeat allele were identical by descent and that the geographic distribution of this allele had not been influenced by natural selection. To investigate whether these assumptions are satisfied, we genotyped 34 SNPs across approximately 500 kilobases (kb) around D9S1120 in 21 Native American and Western Beringian populations and 54 other worldwide populations. All chromosomes with the 9-repeat allele share the same haplotypic background in the vicinity of D9S1120, suggesting that all sampled copies of the 9-repeat allele are identical by descent. Ninety-one percent of these chromosomes share the same 76.26 kb haplotype, which we call the "American Modal Haplotype" (AMH). Three observations lead us to conclude that the high frequency and widespread distribution of the 9-repeat allele are unlikely to be the result of positive selection: 1) aside from its association with the 9-repeat allele, the AMH does not have a high frequency in the Americas, 2) the AMH is not unusually long for its frequency compared to other haplotypes in the Americas, and 3) in Latin American mestizo populations, the proportion of Native American ancestry at D9S1120 is not unusual compared to that observed at other genomewide microsatellites. Using a new method for estimating the time to the most recent common ancestor (MRCA) of all sampled copies of an allele on the basis of an estimate of the length of the genealogy descended from the MRCA, we calculate the mean time to the MRCA of the 9-repeat allele to be between 7,325 and 39,900 years, depending on the demographic model used. The results support the hypothesis that all modern Native Americans and Western Beringians trace a large portion of their ancestry to a single founding population which may have been isolated from other Asian populations prior to expanding into the Americas.

Discovery of rare variants in regions identified by GWASs

P-ter at GNXP and Dan at Genetic Future discuss what seems to be an interesting and important recently published paper in Science (abstract below) that finds four rare variants with larger-than-usual effects for Type-1 Diabetes. The last line of the abstract pretty much says it all. The evolutionary interpretation is of course very interesting, especially since the rare variants reduce risk. Dan talks about this.

Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes
Sergey Nejentsev, Neil Walker , David Riches, Michael Egholm, John A. Todd
Science DOI: 10.1126/science.1167728

Abstract: Genome-wide association studies (GWAS) are widely used to map genomic regions contributing to common human diseases, but they often do not identify the precise causative genes and sequence variants. To identify causative type 1 diabetes (T1D) variants, we resequenced exons and splice sites of ten candidate genes in pools of DNA from 480 patients and 480 controls and tested their disease association in over 30,000 subjects. We discovered four rare variants that lowered T1D risk independently of each other (OR = 0.51 – 0.74; P = 1.3 x 10-3 – 2.1 x 10-16) in IFIH1, a gene located in a region previously associated with T1D by GWAS. These variants are predicted to alter the expression and structure of IFIH1 (MDA5), a cytoplasmic helicase that mediates induction of interferon response to viral RNA. This firmly establishes the role of IFIH1 in T1D and demonstrates that resequencing studies can pinpoint disease-causing genes in genomic regions initially identified by GWAS.

Introgression of black coat color into wolves from dogs

Molecular and Evolutionary History of Melanism in North American Gray Wolves
Tovi M. Anderson, Bridgett M. vonHoldt, Sophie I. Candille, Marco Musiani, Claudia Greco, Daniel R. Stahler, Douglas W. Smith, Badri Padhukasahasram, Ettore Randi, Jennifer A. Leonard, Carlos D. Bustamante, Elaine A. Ostrander, Hua Tang, Robert K. Wayne, Gregory S. Barsh
Science 6 March 2009: Vol. 323. no. 5919, pp. 1339 - 1343

Abstract: Morphological diversity within closely related species is an essential aspect of evolution and adaptation. Mutations in the Melanocortin 1 receptor (Mc1r) gene contribute to pigmentary diversity in natural populations of fish, birds, and many mammals. However, melanism in the gray wolf, Canis lupus, is caused by a different melanocortin pathway component, the K locus, that encodes a beta-defensin protein that acts as an alternative ligand for Mc1r. We show that the melanistic K locus mutation in North American wolves derives from past hybridization with domestic dogs, has risen to high frequency in forested habitats, and exhibits a molecular signature of positive selection. The same mutation also causes melanism in the coyote, Canis latrans, and in Italian gray wolves, and hence our results demonstrate how traits selected in domesticated species can influence the morphological diversity of their wild relatives.