Population split time estimation and X to autosome effective population size differences inferred using physically phased genomes

Population split time estimation and X to autosome effective population size differences inferred using physically phased genomes

Shiya Song, Elzbieta Sliwerska, Jeffrey M Kidd
doi: http://dx.doi.org/10.1101/008367

Haplotype resolved genome sequence information is of growing interest due to its applications in both population genetics and medical genetics. Here, we assess the ability to correctly reconstruct haplotype sequences using fosmid pooled sequencing and apply the sequences to explore historical population relationships. We resolved phased haplotypes of sample NA19240, a trio child from the Yoruba HapMap collection using pools of a total of 521,783 fosmid clones. We phased 93% of heterozygous SNPs into haplotype-resolved blocks, with an N50 size of 318kb. Using trio information from HapMap, we linked adjacent blocks together to form paternal and maternal alleles, producing near-to-complete haplotypes. Comparison with 33 individual fosmids sequenced using capillary sequencing shows that our reconstructed sequence haplotypes have a sequence error rate of 0.005%. Utilizing fosmid-phased haplotypes from a Yoruba, a European and a Gujarati sample, we analyzed population history and inferred population split times. We date the initial split between Yoruba and out of African populations to 90,000-100,000 years ago with substantial gene flow occurring until nearly 50,000 years ago, and obtain congruent results with the autosomes and the X chromosome. We estimate that the initial split between European and Gujarati population occurred around 45,000 years ago and gene flow ended around 28,000 years ago. Analysis of X vs autosome inferred effective population sizes reveals distinct epochs in which the ratio of the effective number of males to females changes. We find a period of female bias during the ancestral human lineage up to 1 million years ago and a short period of male bias in Yoruba lineage from 160-400 thousand years ago. We demonstrate the construction of haplotype sequences of sufficient completeness and accuracy for population genetic analysis. As experimental and analytic methods improve, these approaches will continue to shed new light on the history of populations.

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