Abstract
This research investigates the influence of demographic factors on human genetic sub-structure. In our discovery cohort, we show significant demographic trends for decreasing autozygosity associated with population variation in chronological age. Autozygosity, the genomic signature of consanguinity, is identifiable on a genome-wide level as extended tracts of homozygosity. We identified an average of 28.6 tracts of extended homozygosity greater than 1 Mb in length in a representative population of 809 unrelated North Americans of European descent ranging in chronological age from 19–99 years old. These homozygous tracts made up a population average of 42 Mb of the genome corresponding to 1.6% of the entire genome, with each homozygous tract an average of 1.5 Mb in length. Runs of homozygosity are steadily decreasing in size and frequency as time progresses (linear regression, p<0.05). We also calculated inbreeding coefficients and showed a significant trend for population-wide increasing heterozygosity outside of linkage disequilibrium. We successfully replicated these associations in a demographically similar cohort comprised of a subgroup of 477 Baltimore Longitudinal Study of Aging participants. We also constructed statistical models showing predicted declining rates of autozygosity spanning the 20th century. These predictive models suggest a 14.0% decrease in the frequency of these runs of homozygosity and a 24.3% decrease in the percent of the genome in runs of homozygosity, as well as a 30.5% decrease in excess homozygosity based on the linkage pruned inbreeding coefficients. The trend for decreasing autozygosity due to panmixia and larger effective population sizes will likely affect the frequency of rare recessive genetic diseases in the future. Autozygosity has declined, and it seems it will continue doing so.
Highlights
Rates of travel and migration within North America have increased substantially over the past century due to advancements in infrastructure and technology
We have investigated how demographic trends in the past century have been recapitulated in quantifiable genetic changes, and how this may impact medical genetics and genetic diseases
Our research group sought to investigate the intersection of these two disciplines and examine the way in which demographic trends associated with decreasing levels of inbreeding may influence genomic structure and how this may affect medical genetics research
Summary
Rates of travel and migration within North America have increased substantially over the past century due to advancements in infrastructure and technology. We focused our study on genome-wide rates of autozygosity and measured tracts of extended homozygosity in two age-heterogeneous samples of North Americans to estimate the genetic effect possibly attributable to demographic change. We measured autozygosity in the form of runs of extended homozygosity (ROHs) We analyzed these extended tracts of homozygosity genome-wide, showing a strong positive association between increasing chronological age and increasing rates of autozygosity. These homozygous runs were used to quantify consanguinity in our analysis populations. We utilized a modified inbreeding coefficient to quantify decline in the proportion of excess homozygosity outside of linkage disequilibrium This modified inbreeding coefficient, has been calculated using data that has had all neighboring single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium (LD)
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