Parental relatedness through time revealed by runs of homozygosity in ancient DNA.
ABSTRACT: Parental relatedness of present-day humans varies substantially across the globe, but little is known about the past. Here we analyze ancient DNA, leveraging that parental relatedness leaves genomic traces in the form of runs of homozygosity. We present an approach to identify such runs in low-coverage ancient DNA data aided by haplotype information from a modern phased reference panel. Simulation and experiments show that this method robustly detects runs of homozygosity longer than 4 centimorgan for ancient individuals with at least 0.3 × coverage. Analyzing genomic data from 1,785 ancient humans who lived in the last 45,000 years, we detect low rates of first cousin or closer unions across most ancient populations. Moreover, we find a marked decay in background parental relatedness co-occurring with or shortly after the advent of sedentary agriculture. We observe this signal, likely linked to increasing local population sizes, across several geographic transects worldwide.
Project description:The human genome is characterised by many runs of homozygous genotypes, where identical haplotypes were inherited from each parent. The length of each run is determined partly by the number of generations since the common ancestor: offspring of cousin marriages have long runs of homozygosity (ROH), while the numerous shorter tracts relate to shared ancestry tens and hundreds of generations ago. Human populations have experienced a wide range of demographic histories and hold diverse cultural attitudes to consanguinity. In a global population dataset, genome-wide analysis of long and shorter ROH allows categorisation of the mainly indigenous populations sampled here into four major groups in which the majority of the population are inferred to have: (a) recent parental relatedness (south and west Asians); (b) shared parental ancestry arising hundreds to thousands of years ago through long term isolation and restricted effective population size (N(e)), but little recent inbreeding (Oceanians); (c) both ancient and recent parental relatedness (Native Americans); and (d) only the background level of shared ancestry relating to continental N(e) (predominantly urban Europeans and East Asians; lowest of all in sub-Saharan African agriculturalists), and the occasional cryptically inbred individual. Moreover, individuals can be positioned along axes representing this demographic historic space. Long runs of homozygosity are therefore a globally widespread and under-appreciated characteristic of our genomes, which record past consanguinity and population isolation and provide a distinctive record of the demographic history of an individual's ancestors. Individual ROH measures will also allow quantification of the disease risk arising from polygenic recessive effects.
Project description:Both the total amount and the distribution of heterozygous sites within individual genomes are informative about the genetic diversity of the population they belong to. Detecting true heterozygous sites in ancient genomes is complicated by the generally limited coverage achieved and the presence of post-mortem damage inflating sequencing errors. Additionally, large runs of homozygosity found in the genomes of particularly inbred individuals and of domestic animals can skew estimates of genome-wide heterozygosity rates. Current computational tools aimed at estimating runs of homozygosity and genome-wide heterozygosity levels are generally sensitive to such limitations. Here, we introduce ROHan, a probabilistic method which substantially improves the estimate of heterozygosity rates both genome-wide and for genomic local windows. It combines a local Bayesian model and a Hidden Markov Model at the genome-wide level and can work both on modern and ancient samples. We show that our algorithm outperforms currently available methods for predicting heterozygosity rates for ancient samples. Specifically, ROHan can delineate large runs of homozygosity (at megabase scales) and produce a reliable confidence interval for the genome-wide rate of heterozygosity outside of such regions from modern genomes with a depth of coverage as low as 5-6× and down to 7-8× for ancient samples showing moderate DNA damage. We apply ROHan to a series of modern and ancient genomes previously published and revise available estimates of heterozygosity for humans, chimpanzees and horses.
Project description:Genome-wide association studies (GWASs) of major depressive disorder (MDD) have yet to identify variants that surpass the threshold for genome-wide significance. A recent study reported that runs of homozygosity (ROH) are associated with schizophrenia, reflecting a novel genetic risk factor resulting from increased parental relatedness and recessive genetic effects. Here, we explore the possibility of such a recessive model in MDD. In a sample of 9,238 cases and 9,521 controls reported in a recent mega-analysis of 9 GWAS we perform an analysis of ROH and common variants under a recessive model. Since evidence for association with ROH could reflect a recessive mode of action at loci, we also conducted a genome-wide association analyses under a recessive model. The genome-wide association analysis using a recessive model found no significant associations. Our analysis of ROH suggested that there was significant heterogeneity of effect across studies in effect (P = 0.001), and it was associated with genotyping platform and country of origin. The results of the ROH analysis show that differences across studies can lead to conflicting systematic genome-wide differences between cases and controls that are unaccounted for by traditional covariates. They highlight the sensitivity of the ROH method to spurious associations, and the need to carefully control for potential confounds in such analyses. We found no strong evidence for a recessive model underlying MDD.
Project description:Runs of homozygosity (ROH) are important genomic features that manifest when an individual inherits two haplotypes that are identical by descent. Their length distributions are informative about population history, and their genomic locations are useful for mapping recessive loci contributing to both Mendelian and complex disease risk. We have previously shown that ROH, and especially long ROH that are likely the result of recent parental relatedness, are enriched for homozygous deleterious coding variation in a worldwide sample of outbred individuals. However, the distribution of ROH in admixed populations and their relationship to deleterious homozygous genotypes is understudied. Here we analyze whole-genome sequencing data from 1,441 unrelated individuals from self-identified African American, Puerto Rican, and Mexican American populations. These populations are three-way admixed between European, African, and Native American ancestries and provide an opportunity to study the distribution of deleterious alleles partitioned by local ancestry and ROH. We re-capitulate previous findings that long ROH are enriched for deleterious variation genome-wide. We then partition by local ancestry and show that deleterious homozygotes arise at a higher rate when ROH overlap African ancestry segments than when they overlap European or Native American ancestry segments of the genome. These results suggest that, while ROH on any haplotype background are associated with an inflation of deleterious homozygous variation, African haplotype backgrounds may play a particularly important role in the genetic architecture of complex diseases for admixed individuals, highlighting the need for further study of these populations.
Project description:BACKGROUND:Runs of Homozygosity (ROH) are genomic regions where identical haplotypes are inherited from each parent. Since their first detection due to technological advances in the late 1990s, ROHs have been shedding light on human population history and deciphering the genetic basis of monogenic and complex traits and diseases. ROH studies have predominantly exploited SNP array data, but are gradually moving to whole genome sequence (WGS) data as it becomes available. WGS data, covering more genetic variability, can add value to ROH studies, but require additional considerations during analysis. RESULTS:Using SNP array and low coverage WGS data from 1885 individuals from 20 world populations, our aims were to compare ROH from the two datasets and to establish software conditions to get comparable results, thus providing guidelines for combining disparate datasets in joint ROH analyses. By allowing heterozygous SNPs per window, using the PLINK homozygosity function and non-parametric analysis, we were able to obtain non-significant differences in number ROH, mean ROH size and total sum of ROH between data sets using the different technologies for almost all populations. CONCLUSIONS:By allowing 3 heterozygous SNPs per ROH when dealing with WGS low coverage data, it is possible to establish meaningful comparisons between data using SNP array and WGS low coverage technologies.
Project description:Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
Project description:In the presented research, BovineSNP50 microarrays (Illumina) were applied to determine runs of homozygosity in the genomes of 11 cattle breeds maintained in Poland. These cattle breeds represent three basic utility types: milk, meat and dual purpose. Analysis of runs of homozygosity allowed the evaluation of the level of autozygosity within each breed in order to calculate the genomic inbreeding coefficient (FROH), as well as to identify regions of the genome with a high frequency of ROH occurrence, which may reflect traces of directional selectin left in their genomes. Visible differences in the length and distribution of runs of homozygosity in the genomes of the analyzed cattle breeds have been observed. The highest mean number and mean sums of lengths of runs of homozygosity were characteristic for Hereford cattle and intermediate for the Holstein-Friesian Black-and-White variety, Holstein-Friesian Red-and-White variety, Simmental, Limousin, Montbeliarde and Charolais breeds. However, lower values were observed for cattle of conserved breeds. Moreover, the selected livestock differed in the level of inbreeding estimated using the FROH coefficient. In regions of the genome with a high frequency of ROH occurrence, which may reflect the impact of directional selection, a number of genes were observed that can be potentially related to the production traits which are under selection pressure for specific production types. The most important detected genes were GHR, MSTN, DGAT1, FABP4, and TRH, with a known influence on the milk and meat traits of the studied cattle breeds.
Project description:Pikeperch (Sander lucioperca) has emerged as a high value species to the aquaculture industry. However, its farming techniques are at an early stage and its production is often performed without a selective breeding program, potentially leading to high levels of inbreeding. In this study, we identified and characterized autozygosity based on genome-wide runs of homozygosity (ROH) on a sample of parental and offspring individuals, determined effective population size (Ne), and assessed relatedness among parental individuals. A mean of 2,235 ± 526 and 1,841 ± 363 ROH segments per individual, resulting in a mean inbreeding coefficient of 0.33 ± 0.06 and 0.25 ± 0.06 were estimated for the progeny and parents, respectively. Ne was about 12 until four generations ago and at most 106 for 63 generations in the past, with varying genetic relatedness amongst the parents. This study shows the importance of genomic information when family relationships are unknown and the need of selective breeding programs for reproductive management decisions in the aquaculture industry.
Project description:Parental genetic relatedness may lead to adverse health and fitness outcomes in the offspring. However, the degree to which it affects human delivery timing is unknown. We use genotype data from ?25?000 parent-offspring trios from the Norwegian Mother, Father and Child Cohort Study to optimize runs of homozygosity (ROH) calling by maximising the correlation between parental genetic relatedness and offspring ROHs. We then estimate the effect of maternal, paternal, and fetal autozygosity and that of autozygosity mapping (common segments and gene burden test) on the timing of spontaneous onset of delivery. The correlation between offspring ROH using a variety of parameters and parental genetic relatedness ranged between -0.2 and 0.6, revealing the importance of the minimum number of genetic variants included in a ROH and the use of genetic distance. The optimized compared to predefined parameters showed a ?45% higher correlation between parental genetic relatedness and offspring ROH. We found no evidence of an effect of maternal, paternal nor fetal overall autozygosity on spontaneous delivery timing. Yet, through autozygosity mapping, we identified three maternal loci TBC1D1, SIGLECs and EDN1 gene regions reducing median time-to-spontaneous onset of delivery by ?2-5% (P-value< 2.3 × 10-6). We also found suggestive evidence of a fetal locus at 3q22.2, near the RYK gene region (P-value= 2.0 × 10-6). Autozygosity mapping may provide new insights on the genetic determinants of delivery timing beyond traditional genome-wide association studies, but particular and rigorous attention should be given to ROH calling parameter selection.
Project description:It is long known that inbreeding increases the detrimental effects of recessive sequence variants in "Runs of Homozygosity" (ROHs). However, although the phenotypic association of ROH has been investigated for a variety of traits, the statistical power of the results often remains limited as a sufficiently high number of cases are available for only a restricted number of traits. In the present study, we aim to analyze the association of runs of homozygosity with the trait "in-group ethnic favoritism". This analysis assumes that if ethnic identity is important for an individual, that individual may tend to marry more frequently within their own group and therefore ROH are expected to increase. We hypothesize that an attitude preferring one's own ethnic group may be associated with a stronger tendency of inbreeding and, as a result, with more and longer ROHs. Accordingly, we investigated the association between the attitude to someone's own ethnicity and ROH, using the Wisconsin Longitudinal data (WLS, total N ~ 9000) as discovery data set and the Brisbane Twin data as replication data set (N ~ 8000). We find that both the number as well as the total length of homozygous segments are significantly positively associated with "in-group ethnic favoritism", independent of the method used for ROH calculation.