Saturday, March 07, 2009

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.

Friday, March 06, 2009

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.
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