We investigate the consequences of adopting the criteria used by the state of California, as described by Myers et al. (2011), for conducting familial searches. We carried out a simulation study of randomly generated profiles of related and unrelated individuals with 13-locus CODIS genotypes and YFiler® Y-chromosome haplotypes, on which the Myers protocol for relative identification was carried out. For Y-chromosome sharing first degree relatives, the Myers protocol has a high probability ([Formula: see text]) of identifying their relationship. For unrelated individuals, there is a low probability that an unrelated person in the database will be identified as a first-degree relative. For more distant Y-haplotype sharing relatives (half-siblings, first cousins, half-first cousins or second cousins) there is a substantial probability that the more distant relative will be incorrectly identified as a first-degree relative. For example, there is a [Formula: see text] probability that a first cousin will be identified as a full sibling, with the probability depending on the population background. Although the California familial search policy is likely to identify a first degree relative if his profile is in the database, and it poses little risk of falsely identifying an unrelated individual in a database as a first-degree relative, there is a substantial risk of falsely identifying a more distant Y-haplotype sharing relative in the database as a first-degree relative, with the consequence that their immediate family may become the target for further investigation. This risk falls disproportionately on those ethnic groups that are currently overrepresented in state and federal databases.
Summary A total of 3961 married couples from six major geographical areas representing the South Sinai governorates in Egypt were studied to assess the rate of consanguineous marriage. The population of six selected areas (St Catherines, Nuweiba, Abu Rudeis, Ras Sudr, El Tor and Abu Zenima) were subdivided into Bedouin, urban and mixed populations. A questionnaire-based interview was conducted showing that the consanguinity rate in this region is 37.5%, with the highest rate recorded in Abu Rudeis (52.3%) and lowest rate in Nuweiba (24.1%). Consanguinity was significantly higher among the Bedouin population compared with the urban population in Abu Rudeis, Ras Sudr, El Tor and Abu Zenima, while in St Catherines and Nuweiba there was no statistically significant difference. Among consanguineous couples, 5%, 60% and 35% were double first cousins, first cousins and second cousins respectively. The mean inbreeding coefficient α of the studied population was 0.01845.
- Proceedings of the National Academy of Sciences of the United States of America
- Published over 5 years ago
Ancestral environmental exposures have previously been shown to promote epigenetic transgenerational inheritance and influence all aspects of an individual’s life history. In addition, proximate life events such as chronic stress have documented effects on the development of physiological, neural, and behavioral phenotypes in adulthood. We used a systems biology approach to investigate in male rats the interaction of the ancestral modifications carried transgenerationally in the germ line and the proximate modifications involving chronic restraint stress during adolescence. We find that a single exposure to a common-use fungicide (vinclozolin) three generations removed alters the physiology, behavior, metabolic activity, and transcriptome in discrete brain nuclei in descendant males, causing them to respond differently to chronic restraint stress. This alteration of baseline brain development promotes a change in neural genomic activity that correlates with changes in physiology and behavior, revealing the interaction of genetics, environment, and epigenetic transgenerational inheritance in the shaping of the adult phenotype. This is an important demonstration in an animal that ancestral exposure to an environmental compound modifies how descendants of these progenitor individuals perceive and respond to a stress challenge experienced during their own life history.
Close relatives can share large segments of their genome identical by descent (IBD) that can be identified in genome-wide polymorphism datasets. There are a range of methods to use these IBD segments to identify relatives and estimate their relationship. These methods have focused on sharing on the autosomes, as they provide a rich source of information about genealogical relationships. We can hope to learn additional information about recent ancestry through shared IBD segments on the X chromosome, but currently lack the theoretical framework to use this information fully. Here, we fill this gap by developing probability distributions for the number and length of X chromosome segments shared IBD between an individual and an ancestor k generations back, as well as between half- and full-cousin relationships. Due to the inheritance pattern of the X and the fact that X homologous recombination only occurs in females (outside of the pseudoautosomal regions), the number of females along a genealogical lineage is a key quantity for understanding the number and length of the IBD segments shared amongst relatives. When inferring relationships among individuals, the number of female ancestors along a genealogical lineage will often be unknown. Therefore, our IBD segment length and number distributions marginalize over this unknown number of recombinational meioses through a distribution of recombinational meioses we derive. By using Bayes theorem to invert these distributions, we can estimate the number of female ancestors between two relatives, giving us details about the genealogical relations between individuals not possible with autosomal data alone.
- Proceedings of the National Academy of Sciences of the United States of America
- Published about 2 years ago
Nonrandom mating in human populations has important implications for genetics and medicine as well as for economics and sociology. In this study, we performed an integrative analysis of a large cohort of Mexican and Puerto Rican couples using detailed socioeconomic attributes and genotypes. We found that in ethnically homogeneous Latino communities, partners are significantly more similar in their genomic ancestries than expected by chance. Consistent with this, we also found that partners are more closely related-equivalent to between third and fourth cousins in Mexicans and Puerto Ricans-than matched random male-female pairs. Our analysis showed that this genomic ancestry similarity cannot be explained by the standard socioeconomic measurables alone. Strikingly, the assortment of genomic ancestry in couples was consistently stronger than even the assortment of education. We found enriched correlation of partners' genotypes at genes known to be involved in facial development. We replicated our results across multiple geographic locations. We discuss the implications of assortment and assortment-specific loci on disease dynamics and disease mapping methods in Latinos.
The classification of kin into structured groups is a diverse phenomenon which is ubiquitous in human culture. For populations which are organized into large agropastoral groupings of sedentary residence but not governed within the context of a centralised state, such as our study sample of 83 historical Bantu-speaking groups of sub-Saharan Africa, cultural kinship norms guide all aspects of everyday life and social organization. Such rules operate in part through the use of differing terminological referential systems of familial organization. Although the cross-cultural study of kinship terminology was foundational in Anthropology, few modern studies have made use of statistical advances to further our sparse understanding of the structuring and diversification of terminological systems of kinship over time. In this study we use Bayesian Markov Chain Monte Carlo methods of phylogenetic comparison to investigate the evolution of Bantu kinship terminology and reconstruct the ancestral state and diversification of cousin terminology in this family of sub-Saharan ethnolinguistic groups. Using a phylogenetic tree of Bantu languages, we then test the prominent hypothesis that structured variation in systems of cousin terminology has co-evolved alongside adaptive change in patterns of descent organization, as well as rules of residence. We find limited support for this hypothesis, and argue that the shaping of systems of kinship terminology is a multifactorial process, concluding with possible avenues of future research.
BACKGROUND: Characterising genetic diversity through the analysis of massively parallel sequencing (MPS) data offers enormous potential to significantly improve our understanding of the genetic basis for observed phenotypes, including predisposition to and progression of complex human disease. Great challenges remain in resolving which genetic variants are genuinely associated with disease from the millions of ‘bystanders’ and artefactual signals. RESULTS: FAVR is a suite of new methods designed to work with commonly used MPS analysis pipelines to assist in the resolution of some of these issues with a focus on relatively rare genetic variants. To the best of our knowledge, no equivalent has previously been described. The most important and novel aspect of FAVR is the use of signatures in comparator sequence alignment files during variant filtering, and annotation of variants potentially shared between individuals. The FAVR methods use these signatures to facilitate filtering of (i) platform-specific artefacts, (ii) common genetic variants, and, where relevant, (iii) artefacts derived from imbalanced paired-end sequencing, as well as annotation of genetic variants based on evidence of co-occurrence in individuals. By comparing conventional variant calling with or without downstream processing by FAVR methods applied to whole-exome sequencing datasets, we demonstrate a 3-fold smaller rare single nucleotide variant shortlist with no detected reduction in sensitivity. This analysis included Sanger sequencing of rare variant signals not evident in dbSNP131, assessment of known variant signal preservation, and comparison of observed and expected rare variant numbers across a range of first cousin pairs. The principles described herein were applied in our recent publication identifying XRCC2 as a new breast cancer risk gene and have been made publically available as a suite of software tools. CONCLUSIONS: FAVR is a platform-agnostic suite of methods that significantly enhances the analysis of large volumes of sequencing data for the study of rare genetic variants and their influence on phenotypes.
In this paper, the structure of a southeastern Spanish population was studied for the first time with respect to its inbreeding patterns and its relationship with demographic and geographic factors. Data on consanguineous marriages (up to second cousins) from 1900 to 1969 were taken from ecclesiastic dispensations. Our results confirm that the patterns and trends of inbreeding in the study area are consistent with those previously observed in most non-Cantabrian Spanish populations. The rate of consanguineous marriages was apparently stable between 1900 and 1935 and then sharply decreased since 1940, which coincides with industrialization in Spain. A marked departure from Hardy-Weinberg expectations (0.25) in the ratio of first cousin (M22) to second cousin (M33) marriages in the study population (0.88) was observed. The high levels of endogamy (>80%) and its significant steadiness throughout the twentieth century is noteworthy. Accordingly, our results show that exogamous marriages were not only poorly represented but also that this reduced mobility (<6 km) suggests that the choice of a mate was preferentially local. We found higher mobility in M22 with respect to M33 cousin mating. The relationships between population size and consanguinity rates and inbreeding fit power-law distributions. A significant positive correlation was observed between inbreeding and elevation. Many Spanish populations have experienced a prolonged and considerable isolation across generations, which has led to high proportions of historical and local endogamy that is associated, in general, with high [Formula: see text] values. Thus, assessing genomic inbreeding using runs of homozygosity (ROH) in current Spanish populations could be an additional pertinent strategy for obtaining a more refined perspective regarding the population history inferred from the extent and frequency of ROH regions.
The ability to perform whole-exome and, increasingly, whole-genome sequencing on large numbers of individuals has led to increased efforts to identify rare genetic variants that affect the risk of both common and rare diseases. In such applications, it is important to identify families that are segregating the rare variants of interest. For rare diseases or rare familial forms of common diseases, pedigrees with multiple affected members are clearly harbouring risk variants. For more common diseases, however, it may be unclear whether a family with a few affected members is segregating a familial disease, is the result of multiple sporadic cases, or is a mixture of familial cases and phenocopies. We provide calculations for the probability that a family is harbouring familial disease, presented in general terms that admit working guidelines for selecting families for current sequencing studies. Using examples motivated by our own studies of thyroid cancer and published studies of colorectal cancer, we show that for common diseases, families with exactly two affected first-degree relatives have only a moderate probability of segregating familial disease, but this probability is higher for families with three or more affected relatives, and those families should therefore be prioritised in sequencing studies.
Familial non-medullary thyroid cancer (FNMTC) is clinically defined as two or more first-degree relatives with NMTC and appears to follow an autosomal dominant inheritance pattern. Approximately 5-7% of NMTC is hereditary and affects multiple generations with a young age of onset. The primary aim of this study was to determine the age-specific penetrance of NMTC in individuals from a large family with FNMTC with a previously identified private mutation at 4q32, with a secondary aim to determine the penetrance for benign thyroid disease in this family. We present a large family with NMTC in which we had previously described a culpable mutation. Participants provided their personal medical history and family history. The germline 4q32 A > C mutation was detected in 34 of 68 tested individuals. Age-specific penetrance of thyroid cancer and benign thyroid disease was determined using the inverted Kaplan-Meier method of segregation analysis. Individuals who tested positive for the 4q32 mutation have a 68.9% (95% CI 46.5-88.7) risk of developing thyroid cancer by age 70 and a 65.3% (95% CI 46.0-83.8) risk of developing benign thyroid disease by age 70. The 4q32 A > C mutation significantly increases the risk to develop thyroid cancer but not benign thyroid disease in members of this family. The female:male sex ratio of 1.33 that we observed in affected mutation carriers differs greatly from the ratio of approximately 3:1 observed in PTC, supporting a central role of the mutation. Early thyroid surveillance with annual ultrasound is recommended to individuals testing positive for this private familial mutation.