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Genome-wide association studies (GWAS) conducted using commercial single nucleotide polymorphisms (SNP) arrays have proven to be a powerful tool for the detection of common disease susceptibility variants. However, their utility for the detection of lower frequency variants is yet to be practically investigated. Here we describe the application of a rare variant collapsing method to a large genome-wide SNP dataset, the Wellcome Trust Case Control Consortium rheumatoid arthritis (RA) GWAS. We partitioned the data into gene-centric bins and collapsed genotypes of low frequency variants (defined here as MAF ≤0.05) into a single count coupled with univariate analysis. We then prioritised gene regions for further investigation in an independent cohort of 3,355 cases and 2,427 controls based on rare variant signal p value and prior evidence to support involvement in RA. A total of 14,536 gene bins were investigated in the primary analysis and signals mapping to the TNFAIP3 and chr17q24 loci were selected for further investigation. We detected replicating association to low frequency variants in the TNFAIP3 gene (combined p = 6.6 × 10). Even though rare variants are not well-represented and can be difficult to genotype in GWAS, our study supports the application of low frequency variant collapsing methods to genome-wide SNP datasets as a means of exploiting data that are routinely ignored. [ABSTRACT FROM AUTHOR]

The Peutz–Jeghers Syndrome (PJS) is an autosomal dominant polyposis disorder with increased risk of multiple cancers. STK11/ LKB1 (hereafter named STK11) germline mutations account for the large majority of PJS cases whereas large deletions account for about 30% of the cases. We report here the first thorough molecular characterization of 15 large deletions identified in a cohort of 51 clinically well-characterized PJS patients. The deletions were identified by MLPA analysis and characterized by custom CGH-array and quantitative PCR to define their boundaries. The deletions, ranging from 2.9 to 180 kb, removed one or more loci contiguous to the STK11 gene in six patients, while partial STK11 gene deletions were present in the remaining nine cases. By means of DNA sequencing, we were able to precisely characterize the breakpoints in each case. Of the 30 breakpoints, 16 were located in Alu elements, revealing non-allelic homologous recombination (NAHR) as the putative mechanism for the deletions of the STK11 gene, which lays in a region with high Alu density. In the remaining cases, other mechanisms could be hypothesized, such as microhomology-mediated end-joining (MMEJ) or non-homologous end-joining (NHEJ). In conclusion we here demonstrated the non-random occurrence of large deletions associated with PJS. All our patients had a classical PJS phenotype, which shows that haploinsufficiency for SBNO2, C19orf26, ATP5D, MIDN, C19orf23, CIRBP, C19orf24,and EFNA2, does not apparently affect their clinical phenotype. [ABSTRACT FROM AUTHOR]

Previous research has suggested that individuals with constitutional hemizygosity of 18q have a higher risk of autistic-like behaviors. We sought to identify genomic factors located on chromosome 18 as well as other loci that correlate with autistic behaviors. One hundred and five individuals with 18q- were assessed by high-resolution oligo aCGH and by parental ratings of behavior on the Gilliam Autism Rating Scale. Forty-five individuals (43%) had scores within the “possibly” or “very likely” categories of risk for an autism diagnosis. We searched for genetic determinants of autism by (1) identifying additional chromosome copy number changes (2) Identifying common regions of hemizygosity on 18q, and (3) evaluating four regions containing candidate genes located on 18q ( MBD1, TCF4, NETO1, FBXO15). Three individuals with a “very likely” probability of autism had a captured 17p telomere in addition to the 18q deletion suggesting a possible synergy between hemizygosity of 18q and trigosity of 17p. In addition, two of the individuals with an 18q deletion and a “very likely” probability of autism rating had a duplication of the entire short arm of chromosome 18. Although no common region of hemizygosity on 18q was identified, analysis of four regions containing candidate genes suggested that individuals were significantly more likely to exhibit autistic-like behaviors if their region of hemizygosity included TCF4, NETO1, and FBXO15 than if they had any other combination of hemizygosity of the candidate genes. Taken together, these findings identify several new potential candidate genes or regions for autistic behaviors. [ABSTRACT FROM AUTHOR]

Copy number variants (CNVs) of the Williams–Beuren syndrome (WBS) 7q11.23 region are responsible for neurodevelopmental disorders with multi-system involvement and variable expressivity. Typical features of WBS microdeletion comprise a recognizable pattern of facial dysmorphisms, supravalvular aortic stenosis, connective tissue abnormalities, hypercalcemia, and a distinctive neurobehavioral phenotype. Conversely, the phenotype of patients carrying the 7q11.23 reciprocal duplications includes less distinctive facial dysmorphisms and prominent speech delay. The common deletion/duplication ranges in size from 1.5 to 1.8 Mb and encompasses approximately 28 genes. This region is flanked by low copy repeats (LCRs) with greater than ~97% identity, which can mediate non-allelic homologous recombination resulting from misalignment of LCRs during meiosis. A clear genotype–phenotype correlation has been established in WBS only for the elastin gene, which is responsible for the vascular and connective tissue abnormalities. The molecular substrates underlying the other clinical features of 7q11.23 CNVs, including the neurocognitive phenotypes, are still debated. Recent studies suggest that besides the role of the genes in the deleted/duplicated interval, multiple factors such as regulatory sequences, epigenetic mechanisms, parental origin of the CNV, and nucleotide variations in the non-deleted/duplicated allele may be important in determining the variable expressivity of 7q11.23 CNV phenotypes. Here, we review the clinical and molecular findings and the recent insights on genomic disorders associated with CNVs involving the 7q11.23 region. [ABSTRACT FROM AUTHOR]

A recent study reported that Basques do not constitute a genetically distinct population, and that Basques from Spanish and French provinces do not show significant genetic similarity. These conclusions disagree with numerous previous studies, and are not consistent with the historical and linguistic evidence that supports the distinctiveness of Basques. In order to further investigate this controversy, we have genotyped 83 Spanish Basque individuals and used these data to infer population structure based on more than 60,000 single nucleotide polymorphisms of several European populations. Here, we present the first high-throughput analysis including Basques from Spanish and French provinces, and show that all Basques constitute a homogeneous group that can be clearly differentiated from other European populations. [ABSTRACT FROM AUTHOR]

The amelogenin gene on the Y chromosome ( AMELY) is a homolog of the X chromosome amelogenin gene ( AMELX), and the marker is employed for sexing in forensic casework. Deletion of the sequences in the Yp11.2 region containing the AMELY locus has been found in males from various ethnic populations. Two cases of AMELY null males found in the Japanese population had different Y haplogroups and deletion mapping. Proximal and distal breakpoints of a sample of haplogroup D2* were located in TSPYA and TSPYB arrays, respectively, suggesting that the deletion mechanism was non-allelic homologous recombination (NAHR). On the other hand, a sample of haplogroup O3a3c* had the distal breakpoint in the TSPYB array and the proximal breakpoint at position 7.94 Mb, not in the TSPYA array. The likely deletion mechanism is non-homologous end-joining. High-resolution STS mapping in the TSPYB array showed the distal breakpoints differed according to the haplogroups. The deletion length was estimated as 3.1–3.7 Mb and 1.6–1.7 Mb for the sample of haplogroup D2* and O3a3c*, respectively. These deletion events should have occurred independently. [ABSTRACT FROM AUTHOR]

Osteoporosis is characterized by low bone mineral density and structural deterioration of bone tissue, leading to an increased risk of fractures. It is the most common metabolic bone disorder worldwide, affecting one in three women and one in eight men over the age of 50. In the past 15 years, a large number of genes have been reported as being associated with osteoporosis. However, only in the past 4 years we have witnessed an accelerated pace in identifying and validating osteoporosis susceptibility loci. This increase in pace is mostly due to large-scale association studies, meta-analyses, and genome-wide association studies of both single nucleotide polymorphisms and copy number variations. A comprehensive review of these developments revealed that, to date, at least 15 genes ( VDR, ESR1, ESR2, LRP5, LRP4, SOST, GRP177, OPG, RANK, RANKL, COLIA1, SPP1, ITGA1, SP7, and SOX6) can be reasonably assigned as confirmed osteoporosis susceptibility genes, whereas, another >30 genes are promising candidate genes. Notably, confirmed and promising genes are clustered in three biological pathways, the estrogen endocrine pathway, the Wnt/β-catenin signaling pathway, and the RANKL/RANK/OPG pathway. New biological pathways will certainly emerge when more osteoporosis genes are identified and validated. These genetic findings may provide new routes toward improved therapeutic and preventive interventions of this complex disease. [ABSTRACT FROM AUTHOR]

It has been known for over a decade that a majority of men who self report as members of the Jewish priesthood (Cohanim) carry a characteristic Y chromosome haplotype termed the Cohen Modal Haplotype (CMH). The CMH has since been used to trace putative Jewish ancestral origins of various populations. However, the limited number of binary and STR Y chromosome markers used previously did not provide the phylogenetic resolution needed to infer the number of independent paternal lineages that are encompassed within the Cohanim or their coalescence times. Accordingly, we have genotyped 75 binary markers and 12 Y-STRs in a sample of 215 Cohanim from diverse Jewish communities, 1,575 Jewish men from across the range of the Jewish Diaspora, and 2,099 non-Jewish men from the Near East, Europe, Central Asia, and India. While Cohanim from diverse backgrounds carry a total of 21 Y chromosome haplogroups, 5 haplogroups account for 79.5% of Cohanim Y chromosomes. The most frequent Cohanim lineage (46.1%) is marked by the recently reported P58 T->C mutation, which is prevalent in the Near East. Based on genotypes at 12 Y-STRs, we identify an extended CMH on the J-P58* background that predominates in both Ashkenazi and non-Ashkenazi Cohanim and is remarkably absent in non-Jews. The estimated divergence time of this lineage based on 17 STRs is 3,190 ± 1,090 years. Notably, the second most frequent Cohanim lineage (J-M410*, 14.4%) contains an extended modal haplotype that is also limited to Ashkenazi and non-Ashkenazi Cohanim and is estimated to be 4.2 ± 1.3 ky old. These results support the hypothesis of a common origin of the CMH in the Near East well before the dispersion of the Jewish people into separate communities, and indicate that the majority of contemporary Jewish priests descend from a limited number of paternal lineages. [ABSTRACT FROM AUTHOR]

To help unravel some of the early Eurasian steppe migration movements, we determined the Y-chromosomal and mitochondrial haplotypes and haplogroups of 26 ancient human specimens from the Krasnoyarsk area dated from between the middle of the second millennium BC. to the fourth century AD. In order to go further in the search of the geographic origin and physical traits of these south Siberian specimens, we also typed phenotype-informative single nucleotide polymorphisms. Our autosomal, Y-chromosomal and mitochondrial DNA analyses reveal that whereas few specimens seem to be related matrilineally or patrilineally, nearly all subjects belong to haplogroup R1a1-M17 which is thought to mark the eastward migration of the early Indo-Europeans. Our results also confirm that at the Bronze and Iron Ages, south Siberia was a region of overwhelmingly predominant European settlement, suggesting an eastward migration of Kurgan people across the Russo-Kazakh steppe. Finally, our data indicate that at the Bronze and Iron Age timeframe, south Siberians were blue (or green)-eyed, fair-skinned and light-haired people and that they might have played a role in the early development of the Tarim Basin civilization. To the best of our knowledge, no equivalent molecular analysis has been undertaken so far. [ABSTRACT FROM AUTHOR]

Genomic deletions have long been known to play a causative role in microdeletion syndromes. Recent whole-genome genetic studies have shown that deletions can increase the risk for several psychiatric disorders, suggesting that genomic deletions play an important role in the genetic basis of complex traits. However, the association between genomic deletions and common, complex diseases has not yet been systematically investigated in gene mapping studies. Likelihood-based statistical methods for identifying disease-associated deletions have recently been developed for familial studies of parent-offspring trios. The purpose of this study is to develop statistical approaches for detecting genomic deletions associated with complex disease in case–control studies. Our methods are designed to be used with dense single nucleotide polymorphism (SNP) genotypes to detect deletions in large-scale or whole-genome genetic studies. As more and more SNP genotype data for genome-wide association studies become available, development of sophisticated statistical approaches will be needed that use these data. Our proposed statistical methods are designed to be used in SNP-by-SNP analyses and in cluster analyses based on combined evidence from multiple SNPs. We found that these methods are useful for detecting disease-associated deletions and are robust in the presence of linkage disequilibrium using simulated SNP data sets. Furthermore, we applied the proposed statistical methods to SNP genotype data of chromosome 6p for 868 rheumatoid arthritis patients and 1,197 controls from the North American Rheumatoid Arthritis Consortium. We detected disease-associated deletions within the region of human leukocyte antigen in which genomic deletions were previously discovered in rheumatoid arthritis patients. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is caused by trisomy of all or part of human chromosome 21 (HSA21) and is the most common genetic cause of significant intellectual disability. In addition to intellectual disability, many other health problems, such as congenital heart disease, Alzheimer’s disease, leukemia, hypotonia, motor disorders, and various physical anomalies occur at an elevated frequency in people with DS. On the other hand, people with DS seem to be at a decreased risk of certain cancers and perhaps of atherosclerosis. There is wide variability in the phenotypes associated with DS. Although ultimately the phenotypes of DS must be due to trisomy of HSA21, the genetic mechanisms by which the phenotypes arise are not understood. The recent recognition that there are many genetically active elements that do not encode proteins makes the situation more complex. Additional complexity may exist due to possible epigenetic changes that may act differently in DS. Numerous mouse models with features reminiscent of those seen in individuals with DS have been produced and studied in some depth, and these have added considerable insight into possible genetic mechanisms behind some of the phenotypes. These mouse models allow experimental approaches, including attempts at therapy, that are not possible in humans. Progress in understanding the genetic mechanisms by which trisomy of HSA21 leads to DS is the subject of this review. [ABSTRACT FROM AUTHOR]

African descended populations exhibit an increased prevalence of asthma and allergies compared to Europeans. One approach to distinguish between environmental and genetic explanations for this difference is to study relationships of asthma risk to individual admixture. We aimed to determine the admixture proportions of a case-control sample from the Caribbean Coast of Colombia currently participating in genetic studies for asthma, and to test for population stratification and association between African ancestry and asthma and total serum IgE levels (tIgE). We genotyped 368 asthmatics and 365 non-asthmatics for 52 autosomal ancestry informative markers, six mtDNA haplogroups and nine haplogroups and five microsatellites in Y chromosome. Autosomal admixture proportions, population stratification, and associations between ancestry and the phenotypes were estimated by ADMIXMAP. The average admixture proportions among asthmatics were 42.8% European, 39.9% African and 17.2% Native American and among non-asthmatics they were 44.2% ( P = 0.068), 37.6% ( P = 0.007) and 18.1% ( P = 0.050), respectively. In the total sample, the paternal contributions were 71% European, 25% African and 4.0% Native American and the maternal lineages were 56.8% Native American, and 20.2% African; 22.9% of the individuals carried other non-Native American mtDNA haplogroups. African ancestry was significantly associated with asthma (OR: 2.97; 95% CI: 1.08–8.08), high tIgE (OR: 1.9; 95% CI: 1.17–3.12) and socioeconomic status (OR = 0.64; 95% CI: 0.47–0.87). Significant population stratification was observed in this sample. Our findings indicate that genetic factors can explain the association between asthma and African ancestry and suggest that this sample is a useful resource for performing admixture mapping for asthma. [ABSTRACT FROM AUTHOR]

The host genetic basis of differential outcomes in HIV infection, progression, viral load set point and highly active retroviral therapy (HAART) responses was examined for the common Y haplogroups in European Americans and African Americans. Accelerated progression to acquired immune deficiency syndrome (AIDS) and related death in European Americans among Y chromosome haplogroup I (Y-I) subjects was discovered. Additionally, Y-I haplogroup subjects on HAART took a longer time to HIV-1 viral suppression and were more likely to fail HAART. Both the accelerated progression and longer time to viral suppression results observed in haplogroup Y-I were significant after false-discovery-rate corrections. A higher frequency of AIDS-defining illnesses was also observed in haplogroup Y-I. These effects were independent of the previously identified autosomal AIDS restriction genes. When the Y-I haplogroup subjects were further subdivided into six I subhaplogroups, no one subhaplogroup accounted for the effects on HIV progression, viral load or HAART response. Adjustment of the analyses for population stratification found significant and concordant haplogroup Y-I results. The Y chromosome haplogroup analyses of HIV infection and progression in African Americans were not significant. Our results suggest that one or more loci on the Y chromosome found on haplogroup Y-I have an effect on AIDS progression and treatment responses in European Americans. [ABSTRACT FROM AUTHOR]

The role of partial AZFc deletions of the Y chromosome in spermatogenic impairment is currently debated. Recently, it was also reported that duplications of the same region are associated with oligozoospermia in Han-Chinese men. The aims of this study were (1) to evaluate the clinical significance of partial AZFc deletions in a large study population and (2) to define if partial AZFc duplications are a risk factor for spermatogenic failure also in a Caucasian population such as the Italian. We screened 556 infertile patients and 487 normozoospermic controls for partial AZFc deletions with a combined method based on STS+/− followed by CDY1-DAZ gene dosage and copy analysis. For the second aim, we performed CDY1-DAZ gene dosage in 229 infertile patients and 263 normozoospermic controls. The frequency of gr/gr deletions in patients was significantly different from the controls (3.2 vs. 0.4%, respectively; P < 0.001), with an OR = 7.9 (95% CI 1.8–33.8). b2/b3 deletions were rare in both groups (0.5% in patients, 0.2% in controls). Concerning gr/gr duplications, we observed no significant differences in their frequency between cases (2.6%) and controls (3.8%). This is the largest study population in the literature in which all potential methodological and selection biases were carefully avoided to detect the clinical significance of partial AZFc deletions and duplications. Our study provides strong evidence that gr/gr deletion is a risk factor for impaired spermatogenesis, whereas we did not detect a significant effect of b2/b3 deletions and partial AZFc duplications on spermatogenesis in this Caucasian ethnic group. [ABSTRACT FROM AUTHOR]

Hereditary pancreatitis, an autosomal dominant disease with ∼80% penetrance, can be caused by both ‘gain-of-function’ missense and copy number mutations in the cationic trypsinogen gene ( PRSS1). Here we demonstrate a heterozygous hybrid PRSS2 (encoding anionic trypsinogen)/ PRSS1 gene in a French white family with hereditary pancreatitis, by means of quantitative fluorescent multiplex PCR and RT-PCR analyses. The hybrid gene, in which exons 1 and 2 are derived from PRSS2 and exons 3–5 from PRSS1, apparently resulted from a non-allelic homologous recombination (NAHR) event between the chromosome 7 homologs or sister chromatids during meiosis. Interestingly, this hybrid gene causes the disease through a combination of its inherent ‘double gain-of-function’ effect, acting simultaneously as a ‘quantitative’ copy number mutation and a ‘qualitative’ missense mutation (i.e. the known disease-causing p.N29I mutation). Our finding reveals a previously unknown mechanism causing human inherited disease, enriches the lexicon of human genetic variation and goes beyond the known interaction between copy number variations (CNVs) and single nucleotide substitutions in health and disease. Our finding should also stimulate more interest in analyzing both types of genetic variation whenever one tries to determine the contribution of a specific locus to a given disease phenotype. [ABSTRACT FROM AUTHOR]

Small submicroscopic genomic deletions and duplications constitute up to 15% of all mutations underlying human monogenic diseases. In this study, we used newly designed high-resolution oligonucleotide microarrays with a median distance between the probes of 776 bp (average probe interval 2,271 bp) to detect gene deletions in nevoid basal cell carcinoma syndrome (NBCCS) patients. NBCCS, also called Gorlin syndrome, is characterized by developmental defects and tumorigenesis such as medulloblastomas and basal cell carcinomas, caused by mutations of the human patched-1 ( PTCH1) gene. Two out of three deletions could not be detected by a conventional chromosomal analysis. A submicroscopic deletion as small as 165 kb was detected affecting only PTCH1, whereas the other two deletions were much larger (5 and 11 Mb). We demonstrated not only the exact number of genes involved in the deletion but also rapidly determined the junction sequences after pinpointing the breakpoint regions in all individuals analyzed. This report of an array-based determination of junction sequences of long deletions circumvented a labor-intensive analysis such as Southern blotting or FISH. Alu-mediated recombination in one case and non-homologous end joining in the other two were probably implicated in the generation of deletions. This method will contribute to the understanding of molecular pathogenesis of gene deletions as well as rapid genetic testing. [ABSTRACT FROM AUTHOR]

Recently it has been reported that recombination hotspots appear to be highly variable between humans and chimpanzees, and there is evidence for between-person variability in hotspots, and evolutionary transience. To understand the nature of variation in human recombination rates, it is important to describe patterns of variability across populations. Direct measurement of recombination rates remains infeasible on a large scale, and population-genetic approaches can be imprecise, and are affected by demographic history. Reports to date have suggested broad similarity in recombination rates at large genomic scales and across human populations. Here, we examine recombination rate estimates at a finer population and genomic scale: 28 worldwide populations and 107 SNPs in a 1 Mb stretch of chromosome 22q. We employ analysis of variance of recombination rate estimates, corrected for differences in effective population size using genome-wide microsatellite mutation rate estimates. We find substantial variation in fine-scale rates between populations, but reduced variation within continental groups. All effects examined (SNP-pair, region, population and interactions) were highly significant. Adjustment for effective population size made little difference to the conclusions. Observed hotspots tended to be conserved across populations, albeit at varying intensities. This holds particularly for populations from the same region, and also to a considerable degree across geographical regions. However, some hotspots appear to be population-specific. Several results from studies on the population history of humans are in accordance with our analysis. Our results suggest that between-population variation in DNA sequences may underly recombination rate variation. [ABSTRACT FROM AUTHOR]

Selenoprotein S (SEPS1) is a novel candidate gene involved in the regulation of inflammatory response and protection from oxidative damage. This study explored the genetic variation in the SEPS1 locus for an association with CVD as well as with quantitative phenotypes related to obesity and inflammation. We used the case-cohort design and time-to-event analysis in two separate prospectively followed population-based cohorts FINRISK 92 and 97 ( n = 999 and 1,223 individuals, respectively) to study the associations of five single nucleotide polymorphisms with the risk for coronary heart disease (CHD) and ischemic stroke events. We found a significant association with increased CHD risk in females carrying the minor allele of rs8025174 in the combined analysis of both cohorts [hazard ratio (HR) 2.95 (95% confidence interval: 1.37–6.39)]. Another variant, rs7178239, increased the risk for ischemic stroke significantly in females [HR: 3.35 (1.66–6.76)] and in joint analysis of both sexes and both cohorts [HR: 1.75 (1.17–2.64)]. These results indicate that variation in the SEPS1 locus may have an effect on CVD morbidity, especially in females. This observation should stimulate further investigations of the role of this gene and protein in the pathogenesis of CVD. [ABSTRACT FROM AUTHOR]

Amelogenin paralogs on Chromosome X ( AMELX) and Y ( AMELY) are commonly used sexing markers. Interstitial deletion of Yp involving the AMELY locus has previously been reported. The combined frequency of the AMELY null allele in Singapore and Malaysia populations is 2.7%, 0.6% in Indian and Malay ethnic groups respectively. It is absent among 541 Chinese screened. The null allele in this study belongs to 3 Y haplogroups; J2e1 (85.7%), F* (9.5%) and D* (4.8%). Low and high-resolution STS mapping, followed by sequence analysis of breakpoint junction confirmed a large deletion of 3 to 3.7-Mb located at the Yp11.2 region. Both breakpoints were located in TSPY repeat arrays, suggesting a non-allelic homologous recombination (NAHR) mechanism of deletion. All regional null samples shared identical breakpoint sequences according to their haplogroup affiliation, providing molecular evidence of a common ancestry origin for each haplogroup, and at least 3 independent deletion events recurred in history. The estimated ages based on Y-SNP and STR analysis were ∼13.5 ± 3.1 kyears and ∼0.9 ± 0.9 kyears for the J2e1 and F* mutations, respectively. A novel polymorphism G > A at Y-GATA-H4 locus in complete linkage disequilibrium with J2e1 null mutations is a more recent event. This work re-emphasizes the need to include other sexing markers for gender determination in certain regional populations. The frequency difference among global populations suggests it constitutes another structural variation locus of human chromosome Y. The breakpoint sequences provide further information to a better understanding of the NAHR mechanism and DNA rearrangements due to higher order genomic architecture. [ABSTRACT FROM AUTHOR]

Ionizing radiations are known to induce tumors, chromosomal lesions and minisatellite length variations, yet no correlation has been demonstrated between radiation exposure and indels or copy number polymorphism (CNP) of the genes. We studied the impact of natural background radiation (NBR) on the human Y chromosome owing to its haploid status and clonal inheritance. We analyzed the AZFc region using the DNA from blood and semen of 100 males living near the coastal peninsula in Kerala (India), exposed to NBR along with other 50 normal fertile males. STS mapping of AZFc region showed random microdeletions without conclusive gr/gr or b1/b3 phenotypes. Using a highly specific novel Taqman assay based on sY587 sequence, we detected four copies of the DAZ genes in normal males and 4–16 in those exposed to NBR. Amongst NBR exposed males with multiples copies of the DAZ genes, 75% showed varying FISH signals for DAZ genes with cosmid 18E8 whereas 30% showed mosaicism in terms of presence/absence of the signals in 6–8% cells and unexpected number of signals in 9–12% interphase nuclei. Startlingly, all germline samples studied were found to be free from AZFc microdeletions and CNP of the DAZ genes. Since the DAZ genes are heavily implicated with the germ cell development, the cells with DAZ deletion/duplication are unlikely to survive. Alternatively, an innate mechanism may be operative to protect the germline from the effects of NBR. [ABSTRACT FROM AUTHOR]

Admixture mapping is a recently developed method for identifying genetic risk factors involved in complex traits or diseases showing prevalence differences between major continental groups. Type 2 diabetes (T2D) is at least twice as prevalent in Native American populations as in populations of European ancestry, so admixture mapping is well suited to study the genetic basis of this complex disease. We have characterized the admixture proportions in a sample of 286 unrelated T2D patients and 275 controls from Mexico City and we discuss the implications of the results for admixture mapping studies. Admixture proportions were estimated using 69 autosomal ancestry-informative markers (AIMs). Maternal and paternal contributions were estimated from geographically informative mtDNA and Y-specific polymorphisms. The average proportions of Native American, European and, West African admixture were estimated as 65, 30, and 5%, respectively. The contributions of Native American ancestors to maternal and paternal lineages were estimated as 90 and 40%, respectively. In a logistic model with higher educational status as dependent variable, the odds ratio for higher educational status associated with an increase from 0 to 1 in European admixture proportions was 9.4 (95%, credible interval 3.8–22.6). This association of socioeconomic status with individual admixture proportion shows that genetic stratification in this population is paralleled, and possibly maintained, by socioeconomic stratification. The effective number of generations back to unadmixed ancestors was 6.7 (95% CI 5.7–8.0), from which we can estimate that genome-wide admixture mapping will require typing about 1,400 evenly distributed AIMs to localize genes underlying disease risk between populations of European and Native American ancestry. Sample sizes of about 2,000 cases will be required to detect any locus that contributes an ancestry risk ratio of at least 1.5. [ABSTRACT FROM AUTHOR]

The structural microheterogeneity evident between the human and chimpanzee genomes is quite considerable and includes inversions and duplications as well as deletions, ranging in size from a few base-pairs up to several megabases (Mb). Insertions and deletions have together given rise to at least 150 Mb of genomic DNA sequence that is either present or absent in humans as compared to chimpanzees. Such regions often contain paralogous sequences and members of multigene families thereby ensuring that the human and chimpanzee genomes differ by a significant fraction of their gene content. There is as yet no evidence to suggest that the large chromosomal rearrangements which serve to distinguish the human and chimpanzee karyotypes have influenced either speciation or the evolution of lineage-specific traits. However, the myriad submicroscopic rearrangements in both genomes, particularly those involving copy number variation, are unlikely to represent exclusively neutral changes and hence promise to facilitate the identification of genes that have been important for human-specific evolution. [ABSTRACT FROM AUTHOR]

The differential relative contribution of males and females from Africa and Europe to individual African American genomes is relevant to mapping genes utilizing admixture analysis. The assessment of ancestral population contributions to the four types of genomic DNA (autosomes, X and Y chromosomes, and mitochondrial) with their differing modes of inheritance is most easily addressed in males. A thorough evaluation of 93 African American males for 2,018 autosomal single nucleotide polymorphic (SNP) markers, 121 X chromosome SNPs, 10 Y chromosome haplogroups specified by SNPs, and six haplogroup defining mtDNA SNPs is presented. A distinct lack of correlation observed between the X chromosome and the autosomal admixture fractions supports separate treatment of these chromosomes in admixture-based gene mapping applications. The European genetic contributions were highest (and African lowest) for the Y chromosome (28.46%), followed by the autosomes (19.99%), then the X chromosome (12.11%), and the mtDNA (8.51%). The relative order of admixture fractions in the genomic compartments validates previous studies that suggested sex-biased gene flow with elevated European male and African female contributions. There is a threefold higher European male contribution compared with European females (Y chromosome vs. mtDNA) to the genomes of African American individuals meaning that admixture-based gene discovery will have the most power for the autosomes and will be more limited for X chromosome analysis. [ABSTRACT FROM AUTHOR]

The Yakuts (also known as Sakha), Turkic-speaking cattle- and horse-breeders, inhabit a vast territory in Central and northeastern Siberia. On the basis of the archaeological, ethnographic and linguistic evidence, they are assumed to have migrated north from their original area of settlement in the vicinity of Lake Baykal in South Siberia under the pressure of the Mongol expansion during the thirteenth to fifteenth century ad. During their initial migration and subsequent expansion, the ancestors of the Yakuts settled in the territory originally occupied by Tungusic- and Uralic-speaking reindeer-herders and hunters. In this paper we use mtDNA and Y-chromosomal analyses to elucidate whether the Yakut immigration and expansion was accompanied by admixture with the indigenous populations of their new area of settlement or whether the Yakuts displaced the original inhabitants without intermarriage. The mtDNA results show a very close affinity of the Yakuts with Central Asian and South Siberian groups, which confirms their southern origin. There is no conclusive evidence for admixture with indigenous populations, though a small amount cannot be excluded on the basis of the mtDNA data alone. The Y-chromosomal results confirm previous findings of a very strong bottleneck in the Yakuts, the age of which is in good accordance with the hypothesis that the Yakuts migrated north under Mongol pressure. Furthermore, the genetic results show that the Yakuts are a very homogenous population, notwithstanding their current spread over a very large territory. This confirms the historical accounts that they spread over their current area of settlement fairly recently. [ABSTRACT FROM AUTHOR]

In a number of recent studies, we summarized the obvious errors and shortcomings that can be spotted in many (if not most) mitochondrial DNA (mtDNA) data sets published in medical genetics. We have reanalyzed here the complete mtDNA genome data published in various recent reports of East Asian families with hearing impairment, using a phylogenetic approach, in order to demonstrate the persistence of lab-specific mistakes in mtDNA genome sequencing in cases where those caveats were (deliberately) neglected. A phylogenetic reappraisal of complete mtDNAs with mutation A1555G (or G11778A) indeed supports the suggested lack of association between haplogroup background and phenotypic presentation of these mutations in East Asians. In contrast, the claimed pathogenicity of mutation T1095C in Chinese families with hearing impairment seems unsupported, basically because this mutation is rather basal in the mtDNA phylogeny, being specific to haplogroup M11 in East Asia. The roles of other haplogroup specific or associated variants, such as A827G, T961C, T1005C, in East Asian subjects with aminoglycoside-induced and non-syndromic hearing loss are also unclear in view of the known mtDNA phylogeny. [ABSTRACT FROM AUTHOR]

Ireland has one of the oldest systems of patrilineal hereditary surnames in the world. Using the paternal co-inheritance of Y-chromosome DNA and Irish surnames, we examined the extent to which modern surname groups share a common male-line ancestor and the general applicability of Y-chromosomes in uncovering surname origins and histories. DNA samples were collected from 1,125 men, bearing 43 different surnames, and each was genotyped for 17 Y-chromosome short tandem repeat (STR) loci. A highly significant proportion of the observed Y-chromosome diversity was found between surnames demonstrating their demarcation of real and recent patrilineal kinship. On average, a man has a 30-fold increased chance of sharing a 17 STR Y-chromosome haplotype with another man of the same surname but the extent of congruence between the surname and haplotype varies widely between surnames and we attributed this to differences in the number of early founders. Some surnames such as O’Sullivan and Ryan have a single major ancestor, whereas others like Murphy and Kelly have numerous founders probably explaining their high frequency today. Notwithstanding differences in their early origins, all surnames have been extensively affected by later male introgession. None examined showed more than about half of current bearers still descended from one original founder indicating dynamic and continuously evolving kinship groupings. Precisely because of this otherwise cryptic complexity there is a substantial role for the Y-chromosome and a molecular genealogical approach to complement and expand existing sources. [ABSTRACT FROM AUTHOR]

We have analyzed 105 autosomal polymorphic short tandem repeat (STR) loci for nine East and South-eastern Asian populations (two Japanese, five Han Chinese, Thai, and Burmese populations) and a Caucasian population using a multiplex PCR typing system. All the STR loci are genomewide tetranucleotide repeat markers of which the total number of observed alleles and the observed heterozygosity were 756 and 0.743, respectively, for Japanese populations. Phylogenetic analysis for these allele frequency data suggested that the Japanese populations are more closely related with southern Chinese populations than central and/or northern ones. STRUCTURE program analysis revealed the almost clearly divided and accountable population structure at K=2–6, that the two Japanese populations always formed one group separated from the other populations and never belong to different groups at K≥3. Furthermore, our new allele frequency data for 91 loci were analyzed with those for 52 worldwide populations published by previous studies. Phylogenetic and multidimensional scaling (MDS) analyses indicated that Asian populations with large population size (six Han Chinese, three Japanese, two Southeast Asia) formed one distinct cluster and are closer to each other than other ethnic minorities in east and Southeast Asia. This pattern may be the caviar of comparing populations with greatly differing population sizes when STR loci were analyzed. [ABSTRACT FROM AUTHOR]

In order to investigate the genetic history of autochthonous South Siberian populations and to estimate the contribution of distinct patrilineages to their gene pools, we have analyzed 17 Y-chromosomal binary markers (YAP, RPS4Y711, SRY-8299, M89, M201, M52, M170, 12f2, M9, M20, 92R7, SRY-1532, DYS199, M173, M17, Tat, and LLY22 g) in a total sample of 1,358 males from 14 ethnic groups of Siberia (Altaians-Kizhi, Teleuts, Shors, Tuvinians, Todjins, Tofalars, Sojots, Khakassians, Buryats, Evenks), Central/Eastern Asia (Mongolians and Koreans) and Eastern Europe (Kalmyks and Russians). Based on both, the distribution pattern of Y-chromosomal haplogroups and results on AMOVA analysis we observed the statistically significant genetic differentiation between the populations of Baikal and Altai–Sayan regions. We suggest that these regional differences can be best explained by different contribution of Central/Eastern Asian and Eastern European paternal lineages into gene pools of modern South Siberians. The population of the Baikal region demonstrates the prevalence of Central/Eastern Asian lineages, whereas in the populations of Altai and Sayan regions the highest paternal contribution resulted from Eastern European descent is revealed. Yet, our data on Y-chromosome STRs variation demonstrate the clear differences between the South Siberian and Eastern European R1a1-lineages with the evolutionary ages compatible with divergence time between these two regional groups. [ABSTRACT FROM AUTHOR]

Five datasets consisting of samples jointly typed for Y-chromosomal Unique Event Polymorphism (UEP) and simple tandem repeat (STR) markers were re-examined with independent methods for dating the different UEP-defined lineages. We report on the results obtained with an original program which performs comparative dating (BARCODE) in comparison with coalescent analyses performed with BATWING under various prior conditions. For the first time these are equalized across datasets. We also report on the results concerning STR mutability as obtained with both methods. The dating results for the entire series of sub-haplogroups are highly correlated. Within coalescent analyses, dating-estimates under a wide range of priors tend to converge. As to STR mutation rates the main findings are: (1) large variations among loci within the same dataset with both methods, also when the same prior was used for all loci; (2) figures in most cases above 1×10−3 and often above 2×10−3; (3) a few loci that mutate differently across studies. These results closely match those obtained from direct observation of father–son transmissions. Overall, this work supports the use of genetic dating procedures that take into account the complexity of the phenomenon, with a repertoire of priors tailored on the particular dataset. [ABSTRACT FROM AUTHOR]

The inference of the demographic history of populations from genetic variability data is not only of academic interest. It also provides background information for the identification of genes which may have played a role in human evolution or in the aetiology of human disease. To obtain a clear picture of this background, it is necessary to compare data obtained from a number of genomic loci. Due to its very low recombination rate, the NF1 gene region can be regarded as a further suitable locus. A combined resequencing and SNP typing project in a European population disclosed the presence of only two well separated subgroups of NF1 sequences. Statistical analysis revealed a bimodal distribution of the pairwise differences, a positive value of Tajima’s D and a TMRCA of 700,000 years for the whole sample, and pairwise differences indicative for a growing population and TMRCAs of 130,000 to 150,000 years for the subgroups. Together, the data lead to a model that the recent European population went through a bottleneck during the last 150,000 years of its history. Regarding the given timeframe, this bottleneck could either reflect a speciation event which led to the anatomically modern human (AMH), or a severe reduction of the population size during the emigration of AMHs out of Africa or the immigration into Europe. [ABSTRACT FROM AUTHOR]

There is little knowledge on the demographic impact of the western wave of the Bantu expansion. Only some predictions could be made based mainly on indirect archaeological, linguistic, and genetic evidences. Apart from the very limited available data on the mitochondrial DNA (mtDNA) side, there are not, however, Y-chromosome studies revealing–if any–the male contribution of western Bantu-farmers. To elucidate the still poorly characterized western Bantu expansion, we analyzed Y-chromosome (25 biallelic polymorphisms and 15 microsatellite markers) and mtDNA (hypervariable control regions I and II and selected coding region RFLPs) variation in a population of 110 individuals from southwest Africa, and compared it with a database of 2,708 Y-chromosome profiles and of 2,565 mtDNAs from all other regions of Africa. This study reveals (1) a dramatic displacement of male and female Khoisan-speaking groups in the southwest, since both the maternal and the paternal genetic pools were composed exclusively by types carried by Bantu-speakers; (2) a clear bias in the admixture process towards the mating of male Europeans with female Sub-Saharan Africans; (3) the assimilation of east African lineages by the southwest (mainly mtDNA-L3f and Y-chromosome-B2a lineages); and (4) signatures of recent male and female gene flow from the southeast into the southwest. The data also indicate that the western stream of the Bantu expansion was a more gradual process than the eastern counterpart, which likely involved multiple short dispersals. [ABSTRACT FROM AUTHOR]

We have developed a likelihood method to identify moderately distant genealogical relationships from genomewide scan data. The aim is to compare the genotypes of many pairs of people and identify those pairs most likely to be related to one another. We have tested the algorithm using the genotypes of 170 Tasmanians with multiple sclerosis recruited into a haplotype association study. It is estimated from genealogical records that approximately 65% of Tasmania’s current population of 470,000 are direct descendants of the 13,000 female founders living in this island state of Australia in the mid-nineteenth century. All cases and four to five relatives of each case have been genotyped with microsatellite markers at a genomewide average density of 4 cM. Previous genealogical research has identified 51 pairwise relationships linking 56 of the 170 cases. Testing the likelihood calculation on these known relative pairs, we have good power to identify relationships up to degree eight (e.g. third cousins once removed). Applying the algorithm to all other pairs of cases, we have identified a further 61 putative relative pairs, with an estimated false discovery rate of 10%. The power to identify genealogical links should increase when the new, denser sets of SNP markers are used. Except in populations where there is a searchable electronic database containing virtually all genealogical links in the past six generations, the algorithm should be a useful aid for genealogists working on gene-mapping projects, both linkage studies and association studies. [ABSTRACT FROM AUTHOR]

The process by which pastoralism and agriculture spread from the Fertile Crescent over the past 10,000 years has been the subject of intense investigation by geneticists, linguists and archaeologists. However, no consensus has been reached as to whether this Neolithic transition is best characterized by a demic diffusion (with a significant genetic input from migrating farmers) or a cultural diffusion (without substantial migration of farmers). Milk consumption and thus lactose tolerance are assumed to have spread with pastoralism and we propose that by looking at the relevant mutations in and around the lactase gene in human populations, we can gain insight into the origin(s) and spread of dairying. We genotyped the putatively causal allele for lactose tolerance (-13910T) and constructed haplotypes from several polymorphisms in and around the lactase gene (LCT) in three North African Berber populations and compared our results with previously published data. We found that the frequency of the -13910T allele predicts the frequency of lactose tolerance in several Eurasian and North African Berber populations but not in most sub-Saharan African populations. Our analyses suggest that contemporary Berber populations possess the genetic signature of a past migration of pastoralists from the Middle East and that they share a dairying origin with Europeans and Asians, but not with sub-Saharan Africans. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor regarding the article, "On the evolutionary mutation rate at Y-chromosome comments on paper," by Di Giacomo et al, published in the March 17, 2005, of the online issue of the journal, "Human Genetics."

Sex tests based onamelogeninare part of various PCR multiplex reaction kits widely used for human gender identification and have important applications in forensic casework, prenatal diagnosis, DNA databasing and blood sample storage. The two most common sex tests based onamelogeninare represented by primer sets that delimit a 6-bp deletion on the X chromosome to produce X/Y fragments of 106/112 or 212/218 bp, respectively. Few cases ofAMELYdeletion, usually considered as polymorphisms, have been reported so far and a detailed characterization of the molecular alteration is still lacking. In this study, we describe a large interstitial deletion of the Y short arm encompassing theAMELYlocus in two unrelated individuals. The first case was identified in an oligozoospermic, otherwise phenotypically normal, 32-year-old man during the screening for Y microdeletions performed on a sample of infertile males. The second one was found among amniotic liquid samples tested by quantitative fluorescence-polymerase chain reaction and cytogenetic analysis for prenatal diagnosis. The extent of the deletion, spanning approximately 2.5 Mb, was better characterised by pulsed-field gel electrophoresis, followed by fluorescence in situ hybridization and STS marker analysis. [ABSTRACT FROM AUTHOR]

Centromere (centric) fission, also known as transverse or lateral centric misdivision, has been defined as the splitting of one functional centromere of a metacentric or submetacentric chromosome to produce two derivative centric chromosomes. It has been observed in a range of organisms and has been ascribed an important role in karyotype evolution; however, the underlying mechanisms remain unknown. We have investigated four cases of apparent centric fission in humans. Two cases show a missing chromosome 22 or 18 that is replaced by two centric ring products, a third case shows two chromosome-10-derived telocentric chromosomes, whereas a fourth case involves the formation of two chromosome-18-derived isochromosomes. In all four cases, results of gross cytogenetic and fluorescence in situ hybridisation analyses were consistent with a simple centric fission event. However, detailed molecular analyses provided evidence in support of centromere duplication as a predisposing mechanism for the observed chromosomal breakage in two of the cases. Results for the third case are consistent with direct centric fission not involving centromere pre-duplication as the likely mechanism. Insufficient material has precluded the further study of the fourth case. The data provide the first molecular evidence for centromere pre-duplication as a possible mechanism to explain the classically assumed simple “centric fission” events in clinical cytogenetics, karyotype evolution and speciation. [ABSTRACT FROM AUTHOR]

Evidence from rodents and association analyses in humans suggest the presence on chromosome Y of one or more genes affecting blood pressure (BP). TheHindIII centromeric alphoid polymorphism has been reported to be associated with BP in three independent human populations, although other studies reported null associations with this trait. Our objective was to test for association between BP and genetic variation of the Y chromosome. To this end, 2,743 unrelated Caucasian men recruited from nine UK practices were analysed for five SNPs (including theHindIII site) and two microsatellites spanning the non-recombining region of the Y chromosome. Systolic and diastolic BP were analysed both as quantitative traits and as categorical variables. Differences between locations were tested. Haplotypic and linkage disequilibrium (LD) analyses were also performed. Overall, no significant association was found between any of the loci analysed and BP, although post hoc analyses suggest a possible relation of specific Y haplogroups to BP. TheHindIII polymorphism marks major structural differences in the Y centromere which could infuence mitotic loss during ageing, or other somatic events. However, this study does not support a causal effect on BP, although association of one or more Y haplogroups cannot be excluded. [ABSTRACT FROM AUTHOR]

Historical, archaeological and linguistic sources suggest that the ancestors of the present day population in the Faroe Islands may have their origin in several different regions surrounding the North Atlantic Ocean. In this study we use binary and microsatellite markers of the Y chromosome to analyse genetic diversity in the Faroese population and to compare this with the distribution of genotypes in the putative ancestral populations. Using a combination of genetic distance measures, assignment and phylogenetic analyses, we find a high degree of similarity between the Faroese Y chromosomes and the Norwegian, Swedish and Icelandic Y chromosomes but also some similarity with the Scottish and Irish Y chromosomes. Diversity measures and estimates of effective population sizes also suggest that the original gene pool of the settlers have been influenced by random genetic drift, thus complicating direct comparisons with other populations. No extensive immigration from Iceland to the Faroe Islands can be documented in the historical record. We therefore hypothesise that the high degree of Y chromosome similarity between the two populations arose because they were colonised at approximately the same time by males originating from the same regions of Scandinavia and, to a lesser extent, from the British Isles. [ABSTRACT FROM AUTHOR]

Analysis of 89 biallelic polymorphisms in 523 Turkish Y chromosomes revealed 52 distinct haplotypes with considerable haplogroup substructure, as exemplified by their respective levels of accumulated diversity at ten short tandem repeat (STR) loci. The major components (haplogroups E3b, G, J, I, L, N, K2, and R1; 94.1%) are shared with European and neighboring Near Eastern populations and contrast with only a minor share of haplogroups related to Central Asian (C, Q and O; 3.4%), Indian (H, R2; 1.5%) and African (A, E3*, E3a; 1%) affinity. The expansion times for 20 haplogroup assemblages was estimated from associated STR diversity. This comprehensive characterization of Y-chromosome heritage addresses many multifaceted aspects of Anatolian prehistory, including: (1) the most frequent haplogroup, J, splits into two sub-clades, one of which (J2) shows decreasing variances with increasing latitude, compatible with a northward expansion; (2) haplogroups G1 and L show affinities with south Caucasus populations in their geographic distribution as well as STR motifs; (3) frequency of haplogroup I, which originated in Europe, declines with increasing longitude, indicating gene flow arriving from Europe; (4) conversely, haplogroup G2 radiates towards Europe; (5) haplogroup E3b3 displays a latitudinal correlation with decreasing frequency northward; (6) haplogroup R1b3 emanates from Turkey towards Southeast Europe and Caucasia and; (7) high resolution SNP analysis provides evidence of a detectable yet weak signal (<9%) of recent paternal gene flow from Central Asia. The variety of Turkish haplotypes is witness to Turkey being both an important source and recipient of gene flow. [ABSTRACT FROM AUTHOR]

The Y-chromosome haplogroup composition of the population of the Cabo Verde Archipelago was profiled by using 32 single-nucleotide polymorphism markers and compared with potential source populations from Iberia, west Africa, and the Middle East. According to the traditional view, the major proportion of the founding population of Cabo Verde was of west African ancestry with the addition of a minor fraction of male colonizers from Europe. Unexpectedly, more than half of the paternal lineages (53.5%) of Cabo Verdeans clustered in haplogroups I, J, K, and R1, which are characteristic of populations of Europe and the Middle East, while being absent in the probable west African source population of Guiné-Bissau. Moreover, a high frequency of J* lineages in Cabo Verdeans relates them more closely to populations of the Middle East and probably provides the first genetic evidence of the legacy of the Jews. In addition, the considerable proportion (20.5%) of E3b(xM81) lineages indicates a possible gene flow from the Middle East or northeast Africa, which, at least partly, could be ascribed to the Sephardic Jews. In contrast to the predominance of west African mitochondrial DNA haplotypes in their maternal gene pool, the major west African Y-chromosome lineage E3a was observed only at a frequency of 15.9%. Overall, these results indicate that gene flow from multiple sources and various sex-specific patterns have been important in the formation of the genomic diversity in the Cabo Verde islands. [ABSTRACT FROM AUTHOR]

A genome-based investigation of three Muslim populations, the Salar, Bo'an, and Dongxiang, was conducted on 212 individuals (148 males, 64 females) co-resident in Jishisan County, a minority autonomous region located in the province of Gansu, PR China. The Salar are believed to be of Turkic origin, whereas the Bo'an and Dongxiang both speak Mongolian. Biparental dinucleotide markers on chromosomes 13 and 15 indicated elevated mean homozygosity in the Salar (0.32), Bo'an (0.32), and Dongxiang (0.27), equivalent to inbreeding coefficients (Fis) of 0.16; 0.12; 0.01, confirming varying levels of endogamous and consanguineous marriage in all three communities. Y-chromosome unique event polymorphisms (UEPs) showed that males in the three communities shared common ancient origins, with 80–90% of haplotypes in common. However, the high levels of community-specific Y-chromosome STR haplotypes strongly suggested the action(s) of founder effect, genetic drift and preferential consanguinity during more recent historical time. By comparison with the marked inter-community differentiation revealed by the Y-chromosome STRs (29.4%), the mtDNA data indicated similarity between the female lineages of each community with just 1.2% inter-community variation. The combined use of these different marker systems gives an in-depth historical perspective, and provides evidence of past inter-marriage between genetically diverse male founders of each community and Han Chinese females with subsequent community endogamy. [ABSTRACT FROM AUTHOR]

In the second part of my review of the Finnish Disease Heritage (FDH), I discuss the settling of Finland; factors influencing the genes of a population, such as agriculture versus hunting/fishing/gathering, trading and cultural relations, wars and other kinds of violence, and bottlenecks; relatives of the Finns in the light of classical European studies, classical Finnish studies, mtDNA and Y-chromosomal studies; the genes of the Finns today, characterizing FDH, the east-west difference among Finns, and minorities in Finland, viz. the Lapps or Saami and Swedish-speaking Finns. [ABSTRACT FROM AUTHOR]

We report a comparative genetic characterization of two population isolates with parallel demographic histories: the Central Valley of Costa Rica (CVCR) and Antioquia (in northwest Colombia). The analysis of mtDNA, Y-chromosome and autosomal polymorphisms shows that Antioquia and the CVCR are genetically very similar, indicating that closely related parental populations founded these two isolates. In both populations, the male ancestry is predominantly European, whereas the female ancestry is mostly Amerind. In agreement with their isolation, the Amerindian mtDNA diversity of Antioquia and the CVCR is typical of ethnically-defined native populations and is markedly lower than in other Latin American populations. A comparison of linkage disequilibrium (LD) at 18 marker pairs in Antioquia and the CVCR shows that markers in LD in both populations are located at short genetic distances (<~1 cM), whereas markers separated by greater distances are in LD only in the CVCR. This difference probably reflects stochastic variation of LD at the limited number of genome regions compared. The genetic similarity of the populations from Antioquia and the CVCR together with differences in LD between them should be exploitable for the identification and fine mapping of shared disease-related gene variants. [ABSTRACT FROM AUTHOR]

A previous analysis of mtDNA variation in the Caucasus found that Indo-European-speaking Armenians and Turkic-speaking Azerbaijanians were more closely related genetically to other Caucasus populations (who speak Caucasian languages) than to other Indo-European or Turkic groups, respectively. Armenian and Azerbaijanian therefore represent language replacements, possibly via elite dominance involving primarily male migrants, in which case genetic relationships of Armenians and Azerbaijanians based on the Y-chromosome should more closely reflect their linguistic relationships. We therefore analyzed 11 bi-allelic Y-chromosome markers in 389 males from eight populations, representing all major linguistic groups in the Caucasus. As with the mtDNA study, based on the Y-chromosome Armenians and Azerbaijanians are more closely-related genetically to their geographic neighbors in the Caucasus than to their linguistic neighbors elsewhere. However, whereas the mtDNA results show that Caucasian groups are more closely related genetically to European than to Near Eastern groups, by contrast the Y-chromosome shows a closer genetic relationship with the Near East than with Europe. [ABSTRACT FROM AUTHOR]

Haplotype diversity in a genomic region of ~70 kb in 1q21 between genes PKLR and GBA was characterized by typing one single nucleotide polymorphism (SNP) in PKLR, two SNPs in GBA and one short tandem repeat polymorphism (STRP) in PKLR in 1792 chromosomes from 17 worldwide populations. Two other SNPs in GBA were typed in three African populations. Most chromosomes carried one of either two phylogenetically distinct haplotypes with different alleles at each site. Allele diversity at the STRP was tightly linked to haplotype background. Linkage disequilibrium (LD) was highly significant for all SNP pairs in all populations, although it was, on average, slightly higher in non-African populations than in sub-Saharan Africans. Variation at PKLR-GBA was also tightly linked to that at the GBA pseudogene, 16 kb downstream from GBA. Thus, a 90 kb-long LD block was observed, which points to a low recombination rate in this region. Detailed haplotype phylogeny suggests that the chimpanzee GBA haplotype is not one of the two most frequent haplotypes. Based on variability at the PKLR STRP and on the geographical distribution of LD, the expansion of the two main haplotypes may have predated the "Out of Africa" expansion of anatomically modern humans. LD and STRP variability in non-Africans are ∼87% of those in Africans, in contrast with other loci; this implies that the "out of Africa" bottleneck may have had a broad distribution of effects across loci. [ABSTRACT FROM AUTHOR]

Gene frequencies of eight Siberian populations (Mansi, Tuva, Todja, Tofalar, Buryat, Okhotsk Evenki, Ulchi, and Negidal) were determined for the three most polymorphic HLA class II loci (DRB1, DQA1, and DQB1) by a combination of single-stranded conformational polymorphism typing and DNA sequencing. The number of alleles per population ranged from 16 to 25, from seven to eight, and from nine to 14 for the DRB1, DQA1, and DQB1 loci, respectively. The alleles at the three loci occurred in 66 different combinations (haplotypes), most of which appeared to be of ancient origin, but some may have arisen within the Siberian populations. Phylogenetic analysis of the frequency data suggests that the HLA genes of Asian and indigenous American populations stem from a single pool distinct from the gene pools of European and African populations. The Asian populations separate into two clusters, one of which encompasses nearly all the Siberian populations and all the indigenous American populations tested, while the other consists of Central, Eastern, and Southeastern Asian populations. The position of the Tuva people appears to be near the node from which the two clusters diverge. The divergence time of the two clusters is estimated to be 21,000–24,000 years BP. Three different branches of the native Siberian peoples seem to have contributed founders for the indigenous American ethnic groups. [ABSTRACT FROM AUTHOR]

The technical developments and expanded indications for testicular sperm extraction (TESE) with intracytoplasmic sperm injection (ICSI) provide great advantages for patients with non-obstructive azoospermia. Such success, however, also means that genetic abnormalities in non-obstructive azoospermia can be transmitted to the next generation, demonstrating the importance of being able to understand the genetic background of non-obstructive azoospermia. We have previously reported that human leukocyte antigens (HLA)-A33 and -B44 in the HLA class I region and the HLA-DRB1*1302 allele in the HLA class II region are linked to susceptibility to non-obstructive azoospermia in Japanese men. However, strong linkage of HLA-DRB1*1302 with HLA-A33 and -B44 is also evident in the Japanese population. Thus, uncertainty prevails as to whether the HLA class I or class II molecule is more directly associated with non-obstructive azoospermia. In the present study, we performed association analysis with 21 polymorphic microsatellite markers identified near the HLA genes to map the gene involved in the development of non-obstructive azoospermia more precisely. Microsatellite markers located in the HLA class I region or the class III region showed no statistically significant association with this disorder, although once again the HLA-A33 and -B44 alleles showed a significant association. In contrast, some of the microsatellite markers in the HLA class II region and at the HLA-DRB1 and -DQB1 loci displayed strong associations with non-obstructive azoospermia. Taken together, our previous and present data suggest that the critical region for development of non-obstructive azoospermia is near the HLA-DRB1 and -DQB1 segments in the HLA class II region. [ABSTRACT FROM AUTHOR]

DNA variation on the non-recombining portion of the Y chromosome was examined in 610 male samples from 14 global populations in north, east, and southeast Asia, and other regions of the world. Eight haplotypes were observed by analyses of seven biallelic polymorphic markers (DYS257108, DYS287, SRY4064, SRY10831, RPS4Y711, M9, and M15) and were unevenly distributed among the populations. Maximum parsimony tree for the eight haplotypes showed that these haplotypes could be classified into four distinct lineages characterized by three key mutations: an insertion of the Y Alu polymorphic (YAP) element at DYS287, a C-to-G transversion at M9, and a C-to-T transition at RPS4Y711. Of the four lineages, three major lineages (defined by the allele of YAP+, M9-G, and RPS4Y-T, respectively) accounted for 98.6% of the Asian populations studied, indicating that these three paternal lineages have contributed to the formation of modern Asian populations. Moreover, phylogenetic analysis revealed three monophyletic Asian clusters, which consisted of north Asian, Japanese, and Han Chinese/southeast Asian populations, respectively. Coalescence analysis in the haplotype tree showed that the estimated ages for three key mutations ranged from 53,000 to 95,000 years, suggesting that the three lineages were separated from one another during early stages of human evolutionary history. The distribution patterns of the Y-haplotypes and mutational ages for the key markers suggest that three major groups with different paternal ancestries separately migrated to prehistoric east and southeast Asia. [ABSTRACT FROM AUTHOR]

There are various conflicting hypotheses regarding the origins of the tribal groups of India, who belong to three major language groups – Austro-Asiatic, Dravidian and Tibeto-Burman. To test some of the major hypotheses we designed a genetic study in which we sampled tribal populations belonging to all the three language groups. We used a set of autosomal DNA markers, mtDNA restriction-site polymorphisms (RSPs) and mtDNA hypervariable segment-1 (HVS-1) sequence polymorphisms in this study. Using the unlinked autosomal markers we found that there is a fair correspondence between linguistic and genomic affinities among the Indian tribal groups. We reconstructed mtDNA RSP haplotypes and found that there is extensive haplotype sharing among all tribal populations. However, there is very little sharing of mtDNA HVS-1 sequences across populations, and none across language groups. Haplogroup M is ubiquitous, and the subcluster U2i of haplogroup U occurs in a high frequency. Our analyses of haplogroup and HVS-1 sequence data provides evidence in support of the hypothesis that the Austro-Asiatic speakers are the most ancient inhabitants of India. Our data also support the earlier finding that some of the western Eurasian haplogroups found in India may have been present in India prior to the entry of Aryan speakers. However, we do not find compelling evidence to support the theory that haplogroup M was brought into India on an "out of Africa" wave of migration through a southern exit route from Ethiopia. On the contrary, our data raise the possibility that this haplogroup arose in India and was later carried to East Africa from India. [ABSTRACT FROM AUTHOR]

Linkage disequilibrium (LD) between alleles on the same human chromosome results from various evolutionary processes and is thus telling about the history of populations. Recently, LD has garnered substantial interest for its value to map and fine-map disease genes. We examine the distribution of LD between short tandem repeat alleles on autosomes and sex chromosomes in the Remote Oceanic population of Palau to evaluate whether the data are consistent with a recent hypothesis about the origins of genetic variation in Palau, specifically that the population experienced extensive male-biased gene flow following initial settlement. Consistent with evolutionary theory based on effective population size, LD between X-linked alleles is stochastically greater than LD between autosomal alleles, however, small but detectable LD occurs for autosomal markers separated by substantial distances. By contrast, while Y-linked alleles experience only one-third the effective population size of X-linked alleles, their mean value for pairwise LD is only slightly larger than X-linked alleles. For a small population known to experience at least two extreme bottlenecks, 56 six-locus Y haplotypes exhibit remarkable diversity (0.96), comparable to Y diversity of Europeans, however, autosomal and X-linked markers display significantly less diversity, as measured by heterozygosity (4.1% less). Palauan Y haplotypes also fall into distinct clusters, again unlike that of Europe. We argue these data are consistent with waves of male-biased gene flow. [ABSTRACT FROM AUTHOR]