Measures of Autozygosity in Decline: Globalization, Urbanization, and Its Implications for Medical Genetics

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.

Linkage Maps of Lowland and Upland Tetraploid Switchgrass Ecotypes

“…Tracts of extended homozygosity which, on average, span 1 to 2 Mb but can be as long as 17.9 Mb have been observed in humans [29,30]. These tracts are found mainly in regions of high linkage disequilibrium and low recombination, and must be present in sufficiently high frequency in the population to sometimes being inherited from both parents by chance.…”

Inferring Individual Inbreeding and Demographic History from Segments of Identity by Descent inFicedulaFlycatcher Genome Sequences

“…Although the frequency and genomic distribution of ROH has been characterized in humans (McQuillan et al 2008(McQuillan et al , 2012Auton et al 2009;Nalls et al 2009;Kirin et al 2010;Nothnagel et al 2010;Polašek et al 2010;Pemberton et al 2012) and commercial livestock or closely related species (Pollinger et al 2011;Purfield et al 2012;Ferenčaković et al 2013;Kim et al 2013;MacLeod et al 2013), we know little about ROH in natural populations of nonmodel organisms where demographic histories and genomic characteristics often differ substantially from humans and livestock. The rapidly increasing availability of genome assemblies and resequencing data in nonmodel organisms now makes it possible to study ROH at a very high resolution in any species.…”

Homozygosity mapping in outbred families with mental retardation

“…Population studies often use a size cutoff value for the detection of regions of homozygosity (ROHs) of 1 Mb. [18][19][20][21] Homozygous mutations in outbred families have been identified in regions as small as 2.1 Mb and mutations in consanguineous families are usually found in large linkage intervals encompassing several to tens of megabases. 14,22 Therefore, we choose to analyze the 10 outbred families with four different ROH size cutoff values, namely 1, 1.5, 2 and 5 Mb.…”

“…The average of 57 ROHs per individual is in line with previous reports showing on average 31 ROHs in healthy individuals (range 0-115 in 2429 individuals). [18][19][20] To test whether the siblings were truly from outbred families, we compared the total amount of genomic homozygosity (all regions 41 Mb) of the siblings with (1) 19 MR patients from consanguineous parents, (2) 817 MR patients from non-consanguineous parents and (3) 159 healthy controls from an outbred population. With Student's t-test, the siblings having on average 178 Mb (SD: 75 Mb) of the genome homozygous, differed significantly (P¼8.34 E-08) from the consanguineous MR patients, who had on average 358 Mb (SD: 98 Mb) of their genome homozygous.…”