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Single-nucleotide variants (SNVs) and copy number variations (CNVs) are the most common genomic variations that cause phenotypic diversity and genetic disorders. MALDI–TOF–MS is a rapid and cost-effective technique for multi-variant genotyping, but it is challenging to efficiently detect CNVs and clustered SNVs, especially to simultaneously detect CNVs and SNVs in one reaction. Herein, a novel strategy termed Target-Allele-Specific Probe Single-Base Extension (TASP-SBE) was devised to efficiently detect CNVs and clustered SNVs with MALDI–TOF–MS. By comprehensive use of traditional SBE and TASP-SBE strategies, a MALDI–TOF–MS assay was also developed to simultaneously detect 28 α-/β-thalassemia mutations in a single reaction system, including 4 α-thalassemia deletions, 3 HBA and 21 HBB SNVs. The results showed that all 28 mutations were sensitively identified, and the CNVs of HBA/HBB genes were also accurately analyzed based on the ratio of peak height (RPH) between the target allele and reference gene. The double-blind evaluation results of 989 thalassemia carrier samples showed a 100% concordance of this assay with other methods. In conclusion, a one-tube MALDI–TOF–MS assay was developed to simultaneously genotype 28 thalassemia mutations. This novel TASP-SBE was also verified a practicable strategy for the detection of CNVs and clustered SNVs, providing a feasible approach for multi-variants analysis with MALDI–TOF–MS technique. [ABSTRACT FROM AUTHOR]

Single-nucleotide polymorphisms (SNPs) and small genomic regions with multiple SNPs (microhaplotypes, MHs) are rapidly emerging as novel forensic investigative tools to assist in individual identification, kinship analyses, ancestry inference, and deconvolution of DNA mixtures. Here, we analyzed information for 90 microhaplotype loci in 4009 individuals from 79 world populations in 6 major biogeographic regions. The study included multiplex microhaplotype sequencing (mMHseq) data analyzed for 524 individuals from 16 populations and genotype data for 3485 individuals from 63 populations curated from public repositories. Analyses of the 79 populations revealed excellent characteristics for this 90-plex MH panel for various forensic applications achieving an overall average effective number of allele values (Ae) of 4.55 (range 1.04–19.27) for individualization and mixture deconvolution. Population-specific random match probabilities ranged from a low of 10–115 to a maximum of 10–66. Mean informativeness (In) for ancestry inference was 0.355 (range 0.117–0.883). 65 novel SNPs were detected in 39 of the MHs using mMHseq. Of the 3018 different microhaplotype alleles identified, 1337 occurred at frequencies > 5% in at least one of the populations studied. The 90-plex MH panel enables effective differentiation of population groupings for major biogeographic regions as well as delineation of distinct subgroupings within regions. Open-source, web-based software is available to support validation of this technology for forensic case work analysis and to tailor MH analysis for specific geographical regions. [ABSTRACT FROM AUTHOR]

The suite of phenotypic diversity across geographically distributed human populations is the outcome of genetic drift, gene flow, and natural selection throughout human evolution. Human genetic variation underlying local biological adaptations to selective pressures is incompletely characterized. With the emergence of population genetics modeling of large-scale genomic data derived from diverse populations, scientists are able to map signatures of natural selection in the genome in a process known as selection mapping. Inferred selection signals further can be used to identify candidate functional alleles that underlie putative adaptive phenotypes. Phenotypic association, fine mapping, and functional experiments facilitate the identification of candidate adaptive alleles. Functional investigation of candidate adaptive variation using novel techniques in molecular biology is slowly beginning to unravel how selection signals translate to changes in biology that underlie the phenotypic spectrum of our species. In addition to informing evolutionary hypotheses of adaptation, the discovery and functional annotation of adaptive alleles also may be of clinical significance. While selection mapping efforts in non-European populations are growing, there remains a stark under-representation of diverse human populations in current public genomic databases, of both clinical and non-clinical cohorts. This lack of inclusion limits the study of human biological variation. Identifying and functionally validating candidate adaptive alleles in more global populations is necessary for understanding basic human biology and human disease. [ABSTRACT FROM AUTHOR]

Transmission ratio distortion (TRD) is a phenomenon where parental transmission of disease allele to the child does not follow the Mendelian inheritance ratio. TRD occurs in a sex-of-parent-specific or non-sex-of-parent-specific manner. An offset computed from the transmission probability of the minor allele in control-trios can be added to the loglinear model to adjust for TRD. Adjusting the model removes the inflation in the genotype relative risk (RR) estimate and Type 1 error introduced by non-sex-of-parent-specific TRD. We now propose to further extend this model to estimate an imprinting parameter. Some evidence suggests that more than 1% of all mammalian genes are imprinted. In the presence of imprinting, for example, the offspring inheriting an over-transmitted disease allele from the parent with a higher expression level in a neighboring gene is over-represented in the sample. TRD mechanisms such as meiotic drive and gametic competition occur in a sex-of-parent-specific manner. Therefore, sex-of-parent-specific TRD (ST) leads to over-representation of maternal or paternal alleles in the affected child. As a result, ST may bias the imprinting effect when present in the sample. We propose a sex-of-parent-specific transmission offset in adjusting the loglinear model to account for ST. This extended model restores the correct RR estimates for child and imprinting effects, adjusts for inflation in Type 1 error, and improves performance on sensitivity and specificity compared to the original model without ST offset. We conclude that to correctly interpret the association signal of an imprinting effect, adjustment for ST is necessary to ensure valid conclusions. [ABSTRACT FROM AUTHOR]

The great apes (orangutans, gorillas, chimpanzees, bonobos and humans) descended from a common ancestor around 13 million years ago, and since then their sex chromosomes have followed very different evolutionary paths. While great-ape X chromosomes are highly conserved, their Y chromosomes, reflecting the general lability and degeneration of this male-specific part of the genome since its early mammalian origin, have evolved rapidly both between and within species. Understanding great-ape Y chromosome structure, gene content and diversity would provide a valuable evolutionary context for the human Y, and would also illuminate sex-biased behaviours, and the effects of the evolutionary pressures exerted by different mating strategies on this male-specific part of the genome. High-quality Y-chromosome sequences are available for human and chimpanzee (and low-quality for gorilla). The chromosomes differ in size, sequence organisation and content, and while retaining a relatively stable set of ancestral single-copy genes, show considerable variation in content and copy number of ampliconic multi-copy genes. Studies of Y-chromosome diversity in other great apes are relatively undeveloped compared to those in humans, but have nevertheless provided insights into speciation, dispersal, and mating patterns. Future studies, including data from larger sample sizes of wild-born and geographically well-defined individuals, and full Y-chromosome sequences from bonobos, gorillas and orangutans, promise to further our understanding of population histories, male-biased behaviours, mutation processes, and the functions of Y-chromosomal genes. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms (SNPs) within a genetic region including the first two introns of the gene encoding FTO have consistently been shown to be the strongest genetic factors influencing body mass index (BMI). However, this same also contains several regulatory DNA elements that affect the expression of IRX3 and IRX5, which respectively, are located approximately 500 kb and 1.2 Mbp downstream from the BMI-associated FTO locus. Through these affected regulatory elements, genetic variation at the FTO locus influences adipocyte development leading to decreased thermogenesis and increased lipid storage. These findings provide a genomic model for the functional implications of genetic variations at this locus, and also demonstrate the importance of accounting for chromatin-chromatin interactions when constructing hypotheses for the mechanisms of trait and disease-associated common genetic variants. Several consortia have generated genome-wide datasets describing different aspects of chromatin biology which can be utilized to predict functionality and propose biologically relevant descriptions of specific DNA regions. Here, we review some of the publically available data resources on genome function and organization that can be used to gain an overview of genetic regions of interest and to generate testable hypotheses for future studies. We use the BMI- and obesity-associated FTO locus as a subject as it poses an illustrative example on the value of these resources. We find that public databases strongly support long-range interactions between regulatory elements in the FTO locus with the IRXB cluster genes IRX3 and IRX5. Chromatin configuration capture data also support interactions across a large region stretching across from the RPGRIP1L gene, FTO and the IRXB gene cluster. [ABSTRACT FROM AUTHOR]

African Pygmies are hunter-gatherer populations from the equatorial rainforest that present the lowest height averages among humans. The biological basis and the putative adaptive role of the short stature of Pygmy populations has been one of the most intriguing topics for human biologists in the last century, which still remains elusive. Worldwide convergent evolution of the Pygmy size suggests the presence of strong selective pressures on the phenotype. We developed a novel approach to survey the genetic architecture of phenotypes and applied it to study the genomic covariation between allele frequencies and height measurements among Pygmy and non-Pygmy populations. Among the regions that were most associated with the phenotype, we identified a significant excess of genes with pivotal roles in bone homeostasis, such as PPPT3B and the height associated SUPT3H- RUNX2. We hypothesize that skeletal remodeling could be a key biological process underlying the Pygmy phenotype. In addition, we showed that these regions have most likely evolved under positive selection. These results constitute the first genetic hint of adaptive evolution in the African Pygmy phenotype, which is consistent with the independent emergence of the Pygmy height in other continents with similar environments. [ABSTRACT FROM AUTHOR]