Power to Detect Risk Alleles Using Genome-Wide Tag SNP Panels

Advances in high-throughput genotyping and the International HapMap Project have enabled association studies at the whole-genome level. We have constructed whole-genome genotyping panels of over 550,000 (HumanHap550) and 650,000 (HumanHap650Y) SNP loci by choosing tag SNPs from all populations genotyped by the International HapMap Project. These panels also contain additional SNP content in regions that have historically been overrepresented in diseases, such as nonsynonymous sites, the MHC region, copy number variant regions and mitochondrial DNA. We estimate that the tag SNP loci in these panels cover the majority of all common variation in the genome as measured by coverage of both all common HapMap SNPs and an independent set of SNPs derived from complete resequencing of genes obtained from SeattleSNPs. We also estimate that, given a sample size of 1,000 cases and 1,000 controls, these panels have the power to detect single disease loci of moderate risk (λ ∼ 1.8–2.0). Relative risks as low as λ ∼ 1.1–1.3 can be detected using 10,000 cases and 10,000 controls depending on the sample population and disease model. If multiple loci are involved, the power increases significantly to detect at least one locus such that relative risks 20%–35% lower can be detected with 80% power if between two and four independent loci are involved. Although our SNP selection was based on HapMap data, which is a subset of all common SNPs, these panels effectively capture the majority of all common variation and provide high power to detect risk alleles that are not represented in the HapMap data

Design of a Bovine Low-Density SNP Array Optimized for Imputation

The Illumina BovineLD BeadChip was designed to support imputation to higher density genotypes in dairy and beef breeds by including single-nucleotide polymorphisms (SNPs) that had a high minor allele frequency as well as uniform spacing across the genome except at the ends of the chromosome where densities were increased. The chip also includes SNPs on the Y chromosome and mitochondrial DNA loci that are useful for determining subspecies classification and certain paternal and maternal breed lineages. The total number of SNPs was 6,909. Accuracy of imputation to Illumina BovineSNP50 genotypes using the BovineLD chip was over 97% for most dairy and beef populations. The BovineLD imputations were about 3 percentage points more accurate than those from the Illumina GoldenGate Bovine3K BeadChip across multiple populations. The improvement was greatest when neither parent was genotyped. The minor allele frequencies were similar across taurine beef and dairy breeds as was the proportion of SNPs that were polymorphic. The new BovineLD chip should facilitate low-cost genomic selection in taurine beef and dairy cattle

Past Connectivity but Recent Inbreeding in Cross River Gorillas Determined Using Whole Genomes from Single Hairs

The critically endangered western gorillas (Gorilla gorilla) are divided into two subspecies: the western lowland (G. g. gorilla) and the Cross River (G. g. diehli) gorilla. Given the difficulty in sampling wild great ape populations and the small estimated size of the Cross River gorilla population, only one whole genome of a Cross River gorilla has been sequenced to date, hindering the study of this subspecies at the population level. In this study, we expand the number of whole genomes available for wild western gorillas, generating 41 new genomes (25 belonging to Cross River gorillas) using single shed hairs collected from gorilla nests. By combining these genomes with publicly available wild gorilla genomes, we confirm that Cross River gorillas form three population clusters. We also found little variation in genome-wide heterozygosity among them. Our analyses reveal long runs of homozygosity (>10 Mb), indicating recent inbreeding in Cross River gorillas. This is similar to that seen in mountain gorillas but with a much more recent bottleneck. We also detect past gene flow between two Cross River sites, Afi Mountain Wildlife Sanctuary and the Mbe Mountains. Furthermore, we observe past allele sharing between Cross River gorillas and the northern western lowland gorilla sites, as well as with the eastern gorilla species. This is the first study using single shed hairs from a wild species for whole genome sequencing to date. Taken together, our results highlight the importance of implementing conservation measures to increase connectivity among Cross River gorilla sites

Animal counts for mtDNA-chromosome haplotypes^a by breed.

<p>^<i>a</i>Haplotypes defined by SNP BovineHD320000-0141, -0145, -0180, -0226, -0252, -0312, -0332, -0342, -0354, -0358, -0368, -0384, and -0406.</p><p>^<i>b</i>CCGCAACCGCCCG.</p><p>^<i>c</i>CCGCAAACGCCCG.</p><p>^<i>d</i>CCGCAACAGCCCG.</p><p>^<i>e</i>CCGCAACCACCCG.</p><p>^<i>f</i>CCGCAACCGCCCA.</p><p>^<i>g</i>CAACAACCGCCCG.</p><p>^<i>h</i>AAGAGCAAAAAAG.</p

Imputation accuracy for Bovine3K and BovineLD genotypes.

<p>Imputation was performed for A) Bovine3K and B) BovineLD genotypes using Beagle software (<a href="http://faculty.washington.edu/browning/beagle/beagle.html" target="_blank">http://faculty.washington.edu/browning/beagle/beagle.html</a>); imputation accuracy is reported by single-nucleotide polymorphism (SNP).</p

Accuracy of imputation^a from BovineLD or Bovine3K genotypes to BovineSNP50 genotypes for Australian Holsteins with and without a sire in the reference population^b.

<p>^<i>a</i>Imputation was done using Beagle software (<a href="http://faculty.washington.edu/browning/beagle/beagle.html" target="_blank">http://faculty.washington.edu/browning/beagle/beagle.html</a>).</p><p>^<i>b</i>Reference population included 1,831 animals.</p

Numbers of samples, call rates, and BovineSNP50 concordance for validation of BovineLD single-nucleotide polymorphisms (SNPs) by breed.

<p>^<i>a</i>Concordance was included for animals with BovineSNP50 genotypes; “no calls” (null genotypes) on either BovineSNP50 or BovineLD were excluded from comparison.</p><p>^<i>b</i>NA = not applicable.</p