PROJECT SUMMARY
Sex-bias exists in the human genome in DNA content and gene expression. The human X and Y
chromosomes are useful tools for inferring human demography, and crucial for our understanding of human
health. However, despite the genomics era, X and Y chromosomes are still vastly underutilized, especially in a
genome-wide context. My research has focused on the integration of these chromosomes to build
comprehensive analyses of human history and utilizing an evolutionary approach to characterize sex-bias in
gene expression. Using comparative genomics, we have shown that the human Y chromosome has lost nearly
90% of the gene content it once shared with the X, but that natural selection is still active on the human Y.
Further, we showed that, only when analyzing all regions of the genome together (autosomes, X
chromosomes, and the non-recombining and uni-parentally inherited Y chromosome and mtDNA), could one
infer the relative strength of sex-biased demography along with natural selection, acting across the human
genome. Further, our research supports the theory that the human dosage-compensation mechanism via X-
inactivation, evolved step-wise, in a gene-by-gene specific manner on the X chromosome in response to loss
of functional Y-linked genes. This project will include a three-pronged approach to utilizing and studying sex
chromosome variation across humans. First, we will focus on development and extensive testing of novel
methodology for accurately accounting for technical variation that affects alignment and variant calling on the
sex chromosomes. Current alignment pipelines do not account for the shared homology between the X and Y
chromosome, resulting in mis-mapping of reads between the sex chromosomes and reduced power for variant
calling. Our methodology will incorporate sex chromosome biology to improve variant calling on the sex
chromosomes. Second, we will study truly genome-wide patterns of variation (autosomes, X chromosome, Y
chromosome, and mtDNA) among multiple populations in Kenya. Populations in Africa are the most diverse in
the world, and representation of that diversity is conspicuously absent from global population studies. In
collaboration with anthropologists, who are studying, cultural variation, we will assess how genetically diverse
individuals are, and use patterns of variation across the sex chromosomes and autosomes to infer recent and
ancient demography in these populations. Third, we will study gene expression variation (with an emphasis on
X-linked gene expression and X-inactivation) between the sexes, and between populations in the human
placenta. The placenta is the one organ routinely expelled from the body that also provides a crucial interface
during development, and is not studied in current large-scale tissue expression projects. In collaboration with a
long-term pregnancy outcome study we will generate and comprehensively analyze population-specific sex-
bias in the human placenta. This work will improve methodology for studying sex-linked variation, provide
estimates of sex-biased human demography, and elucidate sex-biased expression in the human placenta.