Recent Radiation within Y‐chromosomal Haplogroup R‐M269 Resulted in High Y‐STR Haplotype Resemblance

Y‐chromosomal short tandem repeats (Y‐STRs) are often used in addition to Y‐chromosomal single‐nucleotide polymorphisms (Y‐SNP) to detect subtle patterns in a population genetic structure. There are, however, indications for Y‐STR haplotype resemblance across different subhaplogroups within haplogroup R1b1b2 (R‐M269) which may lead to erosion in the observation of the population genetic pattern. Hence the question arises whether Y‐STR haplotypes are still informative beyond high‐resolution Y‐SNP genotyping for population genetic studies. To address this question, we genotyped the Y chromosomes of more than 1000 males originating from the West‐European regions of Flanders (Belgium), North‐Brabant and Limburg (the Netherlands) at the highest resolution of the current Y‐SNP tree together with 38 commonly used Y‐STRs. We observed high resemblance of Y‐STR haplotypes between males belonging to different subhaplogroups of haplogroup R‐M269. Several subhaplogroups within R‐M269 could not be distinguished from each other based on differences in Y‐STR haplotype variation. The most likely hypothesis to explain this similarity of Y‐STR haplotypes within the population of R‐M269 members is a recent radiation where various subhaplogroups originated within a relatively short time period. We conclude that high‐resolution Y‐SNP typing rather than Y‐STR typing might be more useful to study population genetic patterns in (Western) Europe.     

Simultaneous Analysis of Hundreds of Y‐Chromosomal SNPs for High‐Resolution Paternal Lineage Classification using Targeted Semiconductor Sequencing

SNPs from the non‐recombining part of the human Y chromosome (Y‐SNPs) are informative to classify paternal lineages in forensic, genealogical, anthropological, and evolutionary studies. Although thousands of Y‐SNPs were identified thus far, previous Y‐SNP multiplex tools target only dozens of markers simultaneously, thereby restricting the provided Y‐haplogroup resolution and limiting their applications. Here, we overcome this shortcoming by introducing a high‐resolution multiplex tool for parallel genotyping‐by‐sequencing of 530 Y‐SNPs using the Ion Torrent PGM platform, which allows classification of 432 worldwide Y haplogroups. Contrary to previous Y‐SNP multiplex tools, our approach covers branches of the entire Y tree, thereby maximizing the paternal lineage classification obtainable. We used a default DNA input amount of 10 ng per reaction but preliminary sensitivity testing revealed positive results from as little as 100 pg input DNA. Furthermore, we demonstrate that sample pooling using barcodes is feasible, allowing increased throughput for lower per‐sample costs. In addition to the wetlab protocol, we provide a software tool for automated data quality control and haplogroup classification. The unique combination of ultra‐high marker density and high sensitivity achievable from low amounts of potentially degraded DNA makes this new multiplex tool suitable for a wide range of Y‐chromosome applications.     

Novel ring chromosome composed of X‐ and Y‐derived material in a girl with manifestations of Ullrich‐Turner syndrome

We present a female infant who has a novel genetic variant of Ullrich‐Turner syndrome. Chromosome analysis on amniotic fluid cells obtained because of ultrasound observation of nuchal thickening showed 45,X in all cells. The infant was born with a low posterior hairline and moderate edema over hands and feet. Postnatal chromosome analysis demonstrated two cell lines—47% of the metaphases were 45,X, but 53% had a ring chromosome in addition to the normal X. FISH studies using alpha satellite probes, an X‐whole‐chromosome‐paint (WCP) probe, and a Y‐cocktail probe determined that the ring was composed of both X and Y sequences. FISH studies also determined that the KAL locus was present on the ring, but that XIST was absent. PCR‐based analysis of lymphocyte DNA documented that the ring contained sequences from both the short and the long arm of the Y chromosome. X‐chromosome analysis using a panel of highly polymorphic markers indicated that the ring contained material derived only from Xp22.1 to Xp21.3. No Xq material was identified on the ring, and androgen receptor‐based X‐inactivation studies suggested that the intact X chromosome was not subject to random X inactivation. Am. J. Med. Genet. 93:343–348, 2000. © 2000 Wiley‐Liss, Inc.     

Molecular dissection of the Y chromosome haplogroup E-M78 (E3b1a): a posteriori evaluation of a microsatellite-network-based approach through six new biallelic markers

The human Y chromosome haplogroup E-M78 (E3b1a) occurs commonly and is distributed in northern and eastern Africa, western Asia, and all of Europe. Previously, only two rarely observed internal biallelic markers (UEPs) were known within the E-M78 clade. Here we report the identification of six novel UEPs that significantly refine the phylogeny of this haplogroup. Then, we evaluate the correspondence between the newly defined sub-haplogroups and the E-M78 haplotype clusters previously identified by an 11-microsatellite loci-based network encompassing 232 chromosomes (Cruciani et al., 2004). We observed considerable correspondence between the trees generated by the two types of markers, but also noted important discrepancies between microsatellite and UEP findings. Overall, this analysis reveals that the currently visible terminal branches of the Y tree still contain a large amount of information, in terms of undiscovered biallelic markers, and that caution is needed when using the microsatellite alleles as surrogates of unique event polymorphisms.     

四川汉族人群Y染色体单倍组及其特点的研究

目的建立四川汉族人群Y染色体单倍组的分布资料。方法应用PCR-限制性片段长度多态性、变性高效液相色谱技术、DNA测序方法对341份四川汉族男性标本Y染色体18个二态位点进行基因分型。结果共观察到14个Y染色体单倍组,其中H2、H4单倍组在四川汉族中被首次证实,N＊、H14单倍组为中国人群首次报道。四川汉族人群Y染色体单倍组分布频率与已报道的中国南方汉族人群相比差异具有统计学意义。结论该研究获得了更为准确的四川汉族人群的Y染色体单倍组分布频率,为生精障碍、前列腺癌和睾丸癌等男性特异性疾病的Y连锁遗传因素研究奠定了基础。     

Mutation rates at Y chromosome specific microsatellites

A collaborative work was carried out by the Spanish and Portuguese ISFG Working Group (GEP-ISFG) to estimate Y-STR mutation rates. Seventeen Y chromosome STR loci (DYS19, DYS385, DYS389I and II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS460, DYS461, DYS635 [GATA C4], GATA H4, and GATA A10) were analyzed in a sample of 3,026 father/son pairs. Among 27,029 allele transfers, 54 mutations were observed, with an overall mutation rate across the 17 loci of 1.998 x 10(-3) (95% CI, 1.501 x 10(-3) to 2.606 x 10(-3)). With just one exception, all of the mutations were single-step, and they were observed only once per gametogenesis. Repeat gains were more frequent than losses, longer alleles were found to be more mutable, and the mutation rate seemed to increase with the father's age. Hum Mutat 26(6), 520-528, 2005. (c) 2005 Wiley-Liss, Inc.     

Y‐Chromosomal Lineages of Latvians in the Context of the Genetic Variation of the Eastern‐Baltic Region

Variations of the nonrecombining Y‐chromosomal region were investigated in 159 unrelated Baltic‐speaking ethnic Latvians from four different geographic regions, using 28 biallelic markers and 12 short tandem repeats. Eleven different haplogroups (hgs) were detected in a regionally homogeneous Latvian population, among which N1c, R1a, and I1 cover more than 85% of its paternal lineages. When compared its closest geographic neighbors, the composition of the Latvian Y‐chromosomal gene pool was found to be very similar to those of Lithuanians and Estonians. Despite the comparable frequency distribution of hg N1c in Latvians and Lithuanians with the Finno‐Ugric‐speaking populations from the Eastern coast of the Baltic Sea, the observed differences in allelic variances of N1c haplotypes between these two groups are in concordance with the previously stated hypothesis of different dispersal ways of this lineage in the region. More than a third of Latvian paternal lineages belong specifically to a recently defined R1a‐M558 hg, indicating an influence from a common source within Eastern Slavic populations on the formation of the present‐day Latvian Y‐chromosome gene pool.     

Separating the post-Glacial coancestry of European and Asian Y chromosomes within haplogroup R1a

Human Y-chromosome haplogroup structure is largely circumscribed by continental boundaries. One notable exception to this general pattern is the young haplogroup R1a that exhibits post-Glacial coalescent times and relates the paternal ancestry of more than 10% of men in a wide geographic area extending from South Asia to Central East Europe and South Siberia. Its origin and dispersal patterns are poorly understood as no marker has yet been described that would distinguish European R1a chromosomes from Asian. Here we present frequency and haplotype diversity estimates for more than 2000 R1a chromosomes assessed for several newly discovered SNP markers that introduce the onset of informative R1a subdivisions by geography. Marker M434 has a low frequency and a late origin in West Asia bearing witness to recent gene flow over the Arabian Sea. Conversely, marker M458 has a significant frequency in Europe, exceeding 30% in its core area in Eastern Europe and comprising up to 70% of all M17 chromosomes present there. The diversity and frequency profiles of M458 suggest its origin during the early Holocene and a subsequent expansion likely related to a number of prehistoric cultural developments in the region. Its primary frequency and diversity distribution correlates well with some of the major Central and East European river basins where settled farming was established before its spread further eastward. Importantly, the virtual absence of M458 chromosomes outside Europe speaks against substantial patrilineal gene flow from East Europe to Asia, including to India, at least since the mid-Holocene.     

Variation in bone mineral density in adults in Poland: age and sex differences

The decline of mineral bone density with age can lead in more extreme cases to osteopenia and osteoporosis, and is therefore one of the aspects of ageing with great medical and social significance. With this idea in mind a study of age changes in the trabecular and, separately, the cortical bone density of the radius was carried out in 1218 females and 405 males, aged 22 to 60 years, all occupationally active inhabitants of the city of Wroclaw, Poland. The technique used was the peripheral Quantitative Computed Tomography (pQCT). It was found that in females bone densities remain relatively stable throughout the period between 22 and 40 years. They then begin to decline slowly, with a rapid decline after the age of 55. A distinctly different pattern was found among males, with bone densities reaching peak values, markedly higher than those in females, in the third decade of life. After this age the bone density values begin to decline at a rapid rate, so that by the age of 60 years mean trabecular and cortical densities in males have decreased to levels almost equivalent to females of equal age. In view of the small size of the male samples, especially in the older age classes, the above results should be treated with caution and confirmed using larger samples.     

High Y‐chromosomal Differentiation Among Ethnic Groups of Dir and Swat Districts,Pakistan

The ethnic groups that inhabit the mountainous Dir and Swat districts of northern Pakistan are marked by high levels of cultural and phenotypic diversity. To obtain knowledge of the extent of genetic diversity in this region, we investigated Y‐chromosomal diversity in five population samples representing the three main ethnic groups residing within these districts, including Gujars, Pashtuns and Kohistanis. A total of 27 Y‐chromosomal short tandem repeats (Y‐STRs) and 331 Y‐chromosomal single nucleotide polymorphisms (Y‐SNPs) were investigated. In the Y‐STRs, we observed very high and significant levels of genetic differentiation in nine of the 10 pairwise between‐group comparisons (R_ST 0.179–0.746), and the differences were mirrored in the Y‐SNP haplogroup frequency distribution. No genetic differences were found between the two Pashtun subethnic groups Tarklanis and Yusafzais (R_ST = 0.000). Utmankhels, also considered Pashtuns culturally, were not closely related to any of the other population samples (R_ST 0.451–0.746). Thus, our findings provide examples of both associations and dissociations between cultural and genetic legacies. When analyzed within a larger continental‐scale context, these five ethnic groups fall mostly outside the previously characterized Y‐chromosomal gene pools of the Indo‐Pakistani subcontinent. Male founder effects, coupled with culturally and topographically based constraints upon marriage and movement, are likely responsible for the high degree of genetic structure in this region.     

Molecular mapping of an idic(Yp) chromosome in an Ullrich‐Turner patient

We describe a woman with Ullrich‐Turner manifestations and a 45,X/46,X,+mar karyotype. Fluorescence in situ hybridization (FISH) and DNA analysis were carried out in order to determine the origin and structure of the marker. FISH showed that the marker was a Y‐derived dicentric chromosome. The breakpoint at Yq11 (interval 6) was mapped using Southern blotting and polymerase chain reaction (PCR). There were no nucleotide alterations in the SRY conserved domain. Histological analysis of the gonads showed an ovarian‐like stroma with no signs of testicular tissue. These findings indicate that the patient was a mosaic 45,X/46,X,idic(Yp) whose phenotypic expression, including sex determination, appeared to have had more influence from the 45,X cell line. Am. J. Med. Genet. 91:95–98, 2000. © 2000 Wiley‐Liss, Inc.     

SRY gene transferred to the long arm of the X chromosome in a Y‐positive XX true hermaphrodite

Yp‐specific sequences, including the testicular determinant gene SRY, have been detected and located in a 46,XX true hermaphrodite individual, using PCR amplification and fluorescent in situ hybridization (FISH). Among different Y chromosome loci tested, it was only possible to detect Yp sequences. The Y‐centromere and Yq sequences were absent. Unexpectedly, the Y fragment was translocated to the long arm of one of the X chromosomes, at the Xq28 level, and the derivative (X) chromosome of the patient lacked q‐telomeric sequences. To our knowledge, this is the first Yp/Xq translocation reported. The coexistence of testicular and ovarian tissue in the patient may have arisen by differential inactivation of the Y‐bearing X chromosome, in which Xq telomeric sequences are missing. The possible origin of the Yp/Xq translocation, during paternal meiosis or in somatic paternal cells, is discussed. Am. J. Med. Genet. 90:25–28, 2000. © 2000 Wiley‐Liss, Inc.     

NLO Behavior of Polymers Containing Y‐Shaped Chromophores

New polyurethanes containing Y‐shaped chromophores, symmetrical derivatives of 4‐(dicyanomethylene)‐2‐methyl‐6‐[p‐(dimethylamino)styryl]‐4H‐pyran, have been prepared. The polymers show high glass transition temperatures (T_g) and a good thermal stability. SHG measurements on poled polymer films of the synthesized polymers have been carried out and a maximum d₃₃ of 15 pm · V^?1 has been found at 1 368 nm fundamental wavelength. Time stability measurements on the most active polymer have shown that after the initial fast relaxation, the d₃₃ value remains constant at 80 °C for 60 d.

     

Gene Conversion Violates the Stepwise Mutation Model for Microsatellites in Y‐Chromosomal Palindromic Repeats

The male‐specific region of the human Y chromosome (MSY) contains eight large inverted repeats (palindromes), in which high‐sequence similarity between repeat arms is maintained by gene conversion. These palindromes also harbor microsatellites, considered to evolve via a stepwise mutation model (SMM). Here, we ask whether gene conversion between palindrome microsatellites contributes to their mutational dynamics. First, we study the duplicated tetranucleotide microsatellite DYS385a,b lying in palindrome P4. We show, by comparing observed data with simulated data under a SMM within haplogroups, that observed heteroallelic combinations in which the modal repeat number difference between copies was large, can give rise to homoallelic combinations with zero‐repeats difference, equivalent to many single‐step mutations. These are unlikely to be generated under a strict SMM, suggesting the action of gene conversion. Second, we show that the intercopy repeat number difference for a large set of duplicated microsatellites in all palindromes in the MSY reference sequence is significantly reduced compared with that for nonpalindrome‐duplicated microsatellites, suggesting that the former are characterized by unusual evolutionary dynamics. These observations indicate that gene conversion violates the SMM for microsatellites in palindromes, homogenizing copies within individual Y chromosomes, but increasing overall haplotype diversity among chromosomes within related groups.     

Seeing the Wood for the Trees: A Minimal Reference Phylogeny for the Human Y Chromosome

During the last few decades, a wealth of studies dedicated to the human Y chromosome and its DNA variation, in particular Y‐chromosome single‐nucleotide polymorphisms (Y‐SNPs), has led to the construction of a well‐established Y‐chromosome phylogeny. Since the recent advent of new sequencing technologies, the discovery of additional Y‐SNPs is exploding and their continuous incorporation in the phylogenetic tree is leading to an ever higher resolution. However, the large and increasing amount of information included in the “complete” Y‐chromosome phylogeny, which now already includes many thousands of identified Y‐SNPs, can be overwhelming and complicates its understanding as well as the task of selecting suitable markers for genotyping purposes in evolutionary, demographic, anthropological, genealogical, medical, and forensic studies. As a solution, we introduce a concise reference phylogeny whereby we do not aim to provide an exhaustive tree that includes all known Y‐SNPs but, rather, a quite stable reference tree aiming for optimal global discrimination capacity based on a strongly reduced set that includes only the most resolving Y‐SNPs. Furthermore, with this reference tree, we wish to propose a common standard for Y‐marker as well as Y‐haplogroup nomenclature. The current version of our tree is based on a core set of 417 branch‐defining Y‐SNPs and is available online at http://www.phylotree.org/Y .     

Identification and characterization of novel rapidly mutating Y‐chromosomal short tandem repeat markers

Short tandem repeat polymorphisms on the male‐specific part of the human Y‐chromosome (Y‐STRs) are valuable tools in many areas of human genetics. Although their paternal inheritance and moderate mutation rate (~10^?3 mutations per marker per meiosis) allow detecting paternal relationships, they typically fail to separate male relatives. Previously, we identified 13 Y‐STR markers with untypically high mutation rates (>10^?2), termed rapidly mutating (RM) Y‐STRs, and showed that they improved male relative differentiation over standard Y‐STRs. By applying a newly developed in silico search approach to the Y‐chromosome reference sequence, we identified 27 novel RM Y‐STR candidates. Genotyping them in 1,616 DNA‐confirmed father–son pairs for mutation rate estimation empirically highlighted 12 novel RM Y‐STRs. Their capacity to differentiate males related by 1, 2, and 3 meioses was 27%, 47%, and 61%, respectively, while for all 25 currently known RM Y‐STRs, it was 44%, 69%, and 83%. Of the 647 Y‐STR mutations observed in total, almost all were single repeat changes, repeat gains, and losses were well balanced; allele length and fathers' age were positively correlated with mutation rate. We expect these new RM Y‐STRs, together with the previously known ones, to significantly improving male relative differentiation in future human genetic applications.