RESUMO
The out-of-Africa scenario has hitherto provided little evidence for the precise route by which modern humans left Africa. Two major routes of dispersal have been hypothesized: one through North Africa into the Levant, documented by fossil remains, and one through Ethiopia along South Asia, for which little, if any, evidence exists. Mitochondrial DNA (mtDNA) can be used to trace maternal ancestry. The geographic distribution and variation of mtDNAs can be highly informative in defining potential range expansions and migration routes in the distant past. The mitochondrial haplogroup M, first regarded as an ancient marker of East-Asian origin, has been found at high frequency in India and Ethiopia, raising the question of its origin. (A haplogroup is a group of haplotypes that share some sequence variations.) Its variation and geographical distribution suggest that Asian haplogroup M separated from eastern-African haplogroup M more than 50,000 years ago. Two other variants (489C and 10873C) also support a single origin of haplogroup M in Africa. These findings, together with the virtual absence of haplogroup M in the Levant and its high frequency in the South-Arabian peninsula, render M the first genetic indicator for the hypothesized exit route from Africa through eastern Africa/western India. This was possibly the only successful early dispersal event of modern humans out of Africa.
Assuntos
Evolução Molecular , Hominidae/genética , África , Animais , Sequência de Bases , Primers do DNA/genética , DNA Mitocondrial/genética , Emigração e Imigração , Feminino , Variação Genética , Genética Populacional , Haplótipos , Humanos , Índia , Masculino , Modelos Genéticos , Polimorfismo de Fragmento de Restrição , Dinâmica Populacional , Fatores de TempoRESUMO
The CD209 gene family that encodes C-type lectins in primates includes CD209 (DC-SIGN), CD209L (L-SIGN) and CD209L2. Understanding the evolution of these genes can help understand the duplication events generating this family, the process leading to the repeated neck region and identify protein domains under selective pressure. We compiled sequences from 14 primates representing 40 million years of evolution and from three non-primate mammal species. Phylogenetic analyses used Bayesian inference, and nucleotide substitutional patterns were assessed by codon-based maximum likelihood. Analyses suggest that CD209 genes emerged from a first duplication event in the common ancestor of anthropoids, yielding CD209L2 and an ancestral CD209 gene, which, in turn, duplicated in the common Old World primate ancestor, giving rise to CD209L and CD209. K(A)/K(S) values averaged over the entire tree were 0.43 (CD209), 0.52 (CD209L) and 0.35 (CD209L2), consistent with overall signatures of purifying selection. We also assessed the Toll-like receptor (TLR) gene family, which shares with CD209 genes a common profile of evolutionary constraint. The general feature of purifying selection of CD209 genes, despite an apparent redundancy (gene absence and gene loss), may reflect the need to faithfully recognize a multiplicity of pathogen motifs, commensals and a number of self-antigens.
Assuntos
Moléculas de Adesão Celular/genética , Evolução Molecular , Lectinas Tipo C/genética , Receptores de Superfície Celular/genética , Sequência de Aminoácidos , Animais , Moléculas de Adesão Celular/química , Humanos , Lectinas Tipo C/química , Mamíferos , Modelos Moleculares , Dados de Sequência Molecular , Primatas , Estrutura Terciária de Proteína , Receptores de Superfície Celular/químicaRESUMO
Y chromosome microdeletions have been reported as a possible genetic factor of male infertility. Despite a large number of studies in this subject, there is still considerable debate and confusion surrounding the role of Y chromosome microdeletions in male infertility. This has been further compounded by observations of Y microdeletions in fertile males. The aim of the present study was to evaluate: 1) the incidence of Y microdeletions in control male population and infertile males, where complete semen and hormonal analysis was available to define whether Y microdeletions are specific for spermatogenic failure or if they can be found also in normospermic men; and 2) whether the suboptimal semen quality reported in Denmark is associated with a higher incidence of Y microdeletions in respect to other populations. Double-blind molecular study of deletions was performed in 138 consecutive patients seeking intracytoplasmic sperm injection treatment, 100 men of known fertility, and 107 young military conscripts from the general Danish population. Microdeletions or gene-specific deletions were not detected in normospermic subjects or in subfertile men with a sperm count of more than 1 x 10(6)/mL. Deletions of the Azoospermia factor (AZF)c region were detected in 17% of individuals with idiopathic azoo/cryptozoospermia and in 7% of individuals with nonidiopathic azoo/cryptozoospermia. The data indicate that: 1) the composition of the study population is the major factor in determining deletion frequency; 2) Y chromosome microdeletions are specifically associated with severe spermatogenic failure; therefore, the protocol described here is reliable for the routine clinical workup of severe male factor infertility; and 3) the frequency of Yq microdeletions in the Danish population is similar to that from other countries and argues against the involvement of microdeletions in the relatively low sperm count of the Danish population.
Assuntos
Deleção de Genes , Hormônios/sangue , Reprodução/fisiologia , Espermatozoides/fisiologia , Cromossomo Y/genética , Adulto , Dinamarca , Método Duplo-Cego , Frequência do Gene , Humanos , Infertilidade Masculina/genética , Infertilidade Masculina/fisiopatologia , Masculino , Espermatogênese/genéticaRESUMO
Microdeletions of the long arm of the human Y chromosome are associated with spermatogenic failure and have been used to define three regions of Yq (AZFa, AZFb, and AZFc) that are recurrently deleted in infertile males. In a blind study we screened 131 infertile males (46 idiopathic and 85 nonidiopathic) for Y chromosome microdeletions. Nineteen percent of idiopathic males, with an apparently normal 46,XY chromosome complement had microdeletions of either the AZFa, AZFb, or AZFc region. There was no strict correlation between the extent or location of the deletion and the phenotype. The AZFb deletions did not include the active RBM gene. Significantly, a high frequency of microdeletions (7%) was found in patients with known causes of infertility and a 46,XY chromosome complement. These included deletions of the AZFb and AZFc regions, with no significant difference in the location or extent of the deletion compared with the former group. It is recommended that all males with reduced or absence sperm counts seeking assisted reproductive technologies be screened for deletions of the Y chromosome.
Assuntos
Deleção de Genes , Frequência do Gene , Infertilidade Masculina/genética , Cromossomo Y/genética , Adulto , DNA/genética , Genótipo , Humanos , Infertilidade Masculina/etiologia , Masculino , Oligospermia/complicações , Fenótipo , Método Simples-CegoRESUMO
We examined a set of populations mainly from Europe but also from the Middle East and North Africa for the three Y-linked microsatellites YCAII, DYS19 (about 1300 individuals) and DYS392 (about 350 individuals). Three markers (YCAII a5-b1 Ht, DYS19-190 bp and DYS392-254 bp) show decreasing gradients of frequency from western Europe towards the Middle East which parallel that of the proto-European 49a,f/TaqI Ht 15. Indeed, a strong linkage disequilibrium between these markers and the 49a,f Ht15 is observed. We therefore suggest that the 49a,f/TaqI Ht15, YCAII a5-b1 Ht, DYS19-190 bp and DYS392-254 bp Y chromosome could represent a component of the proto-European gene pool. This European specific compound haplotype distinctively characterises western Europeans and its very high incidence in these populations (particularly in the Basques) is discussed.
Assuntos
Cromossomo Y , Europa (Continente) , Marcadores Genéticos , Humanos , Desequilíbrio de LigaçãoRESUMO
Magyars imposed their language on Hungarians but seem not to have affected their genetic structure. To better investigate this point, we analysed some mtDNA and Y chromosome polymorphisms in a sample of the Hungarian Palóc who, for historical reasons, could have retained genetic traces of Magyars more than other groups. In addition, we examined a mixed sample from Budapest. About 100 individuals were tested for the markers defining all the European and Asian mtDNA haplogroups and about 50 individuals for some Y chromosome markers, namely the 12f2 and 49a,f/TaqI RFLPs, the YAP insertion, the microsatellites YCAIIa, YCAIIb, DYS19 and the Asian 50f2/C deletion. In the mtDNA analysis only two subjects belonged to the Asian B and M haplogroups. The Y chromosome analyses showed that the Palóc differed from the Budapest sample by the absence of YAP+ allele and by the DYS19 allele distribution; that the proto-European 49a,f Ht 15 and the neolithic 12f2-8Kb were rather uncommon in both groups; that there is a high prevalence of the 49a,f Ht 11 and the YCAII a5-b1; and that the Asian 50f2/C deletion is absent. These results suggest that the influence of Magyars on the Hungarian gene pool has been very low through both females and males and the Hungarian language could be an example of cultural dominance. Alternative explanations are discussed. An expansion centred on YAP-, 49a,f Ht 11 is revealed by the median network based on compound haplotypes. 49a,f Ht 11 could represent either a paleolithic marker of eastern Europe which underwent expansion after the last glacial period, or a marker of the more recent spread of the Yamnaia culture from southern Ukraine.
Assuntos
DNA Mitocondrial/genética , Etnicidade/genética , Pool Gênico , Polimorfismo Genético , Cromossomo Y , Elementos Alu/genética , Feminino , Haplótipos , Humanos , Hungria/etnologia , Masculino , FilogeniaRESUMO
Previous studies on human Y-chromosome polymorphisms in the European populations highlighted the high frequency of the 49a,f/TaqI haplotype 11 and of the Eu19 (M17) lineage in Eastern Europe. To better understand the origin and the evolution of the Eu19, and its relationship with 49a,f Ht11, this study surveyed 2,235 individuals (mainly from Europe and the Middle East) for the 49a,f Ht11 and for many biallelic markers defining the Eu19 lineage. As previously described, the highest frequency of Eu19 was found in Eastern Europe. All the Eu19 Y-chromosomes turned out to be 49a,f Ht11 or its derivatives, the distribution of which suggests that the Eu19/49a,f Ht11 emerged in Ukraine, probably in a Palaeolithic population. Thereafter, the spread of this lineage toward Europe, Asia, and India occurred at different waves over a few thousands years. At present this seems to indicate the influence of the Ukraine Palaeolithic groups in the gene pool of modern populations. For the first time it is possible to make inferences about the evolution of some haplotypes of the 49a,f system. In spite of its unknown molecular base, this is one of the first most informative polymorphisms of the Y chromosome.
Assuntos
Emigração e Imigração , Haplótipos/genética , Polimorfismo Genético , Cromossomo Y/genética , Alelos , Southern Blotting , Europa (Continente)/etnologia , Frequência do Gene , Marcadores Genéticos/genética , Variação Genética , Humanos , Masculino , Repetições de Microssatélites/genética , Oriente Médio/etnologia , Polimorfismo de Fragmento de RestriçãoRESUMO
The human Y chromosome is strictly paternally inherited and, in most of its length, does not recombine during male meiosis. These features make the Y a very useful genetic marker for different purposes. In the last decade, the Y has been increasingly used to investigate the evolution, migrations and range expansions of modern humans. The possibility to construct highly informative Y chromosome haplotypes has also had a significant impact in forensic studies and paternity testing. All these studies assume that the Y chromosome markers used are selectively neutral. However, recent experimental and statistical analyses suggest that both positive and negative selection are acting on the Y chromosome and, consequently, may influence Y chromosome haplotype distribution in the general population. Current data suggest that the effects of selection on patterns of Y chromosome distribution are minimal, however as interest focuses on biological functions of the Y chromosome which have a major impact on male fitness such as fertility, these assumptions may be challenged. This review briefly describes the genes and biological functions of the human Y chromosome and its use in disentangling the origin and history of human populations. An overview of the role of selection acting on the Y chromosome from the perspective of human population histories and disease is given.
Assuntos
Evolução Molecular , Genética Populacional , Cromossomo Y , Anormalidades Congênitas/genética , Medicina Legal , Marcadores Genéticos , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Paternidade , Cromossomo Y/genética , Cromossomo Y/fisiologiaRESUMO
Analysis of mtDNA and Y-chromosome variation in the Indo-Gangetic plains shows that it was a region where genetic components of different geographical origins (from west, east and south) met. The genetic architecture of the populations now living in the area comprise genetic components dating back to different time-periods during the Palaeolithic and the Neolithic. mtDNA data analysis has demonstrated a number of deep-rooting lineages of Pleistocene origin that may be witness to the arrival of the first settlers of South and Southwest Asia after humans left Africa around 60,000 YBP. In addition, comparisons of Y-chromosome and mtDNA data have indicated a number of recent and sexually asymmetrical demographic events, such as the migrations of the Parsis from Iran to India, and the maternal traces of the East African slave trade.
Assuntos
Cromossomos Humanos Y , DNA Mitocondrial/análise , Marcadores Genéticos , Variação Genética , Genética Populacional , Folclore , Humanos , Índia , Idioma , Masculino , Paquistão , FilogeniaRESUMO
Mitochondrial DNA (mtDNA) and the Y chromosome are inherited in a haploid manner and have been used extensively to reconstruct human lineages. mtDNA and the majority of the Y chromosome lack recombination and show high rates of apparently neutral mutation. Here, we demonstrate how detailed analysis of these uniparental inherited markers can reveal general and more subtle population movements within south-west Asia. These include a major migration of modern humans from East Africa to western and southern Asia around 60,000 YBP, migrations of populations from the Fertile Crescent in south-western Iran to India approximately 8,000 YBP, and migrations of Indo-European speakers from Central and West Asia to India approximately 5,000 YBP. We highlight how the understanding of these, and other population movements, can be useful in tracing the dispersal of disease-causing mutant alleles, and how these data could be applied to predicting the segregation of mutant alleles within populations.
RESUMO
Mammals present an XX/XY system of chromosomal sex determination, males being the heterogametic sex. Comparative studies of the gene content of sex chromosomes from the major groups of mammals reveal that most Y genes have X-linked homologues and that X and Y share homologous pseudoautosomal regions. These observations, together with the presence of the two homologous regions (pseudoautosomal regions) at the tips of the sex chromosomes, suggest that these chromosomes began as an ordinary pair of homologous autosomes. Birds present a ZW/ZZ system of chromosomal sex determination where females are the heterogametic sex. In this case, avian sex chromosomes are derived from different pairs of autosomes than mammals. The evolutionary pathway from the autosomal homomorphic departure to the present-day heteromorphic sex chromosomes in mammals includes suppression of X-Y recombination, differentiation of the nascent non-recombining regions, and progressive autosomal addition and attrition of the sex chromosomes. Recent results indicate that the event marking the beginning of the differentiation between the extant X and Y chromosomes occurred about 300 million years ago.
Assuntos
Evolução Molecular , Mamíferos/genética , Cromossomos Sexuais , Animais , Feminino , Masculino , Recombinação GenéticaRESUMO
In many centres, Y chromosome deletion analysis is still not performed routinely and if so, the results are used for genetic counselling but are not considered as having a useful prognostic value. The type of deletion (AZFa, b or c) has been proposed as a potential prognostic factor for sperm retrieval in men undergoing TESE. AZFc deletions and partial AZFb deletions are associated with sperm retrieval in approximately 50% of cases while in the case of a patient with complete AZFb deletion the probability of finding mature spermatozoa is virtually nil. Therefore the extent and position of a Y microdeletion is important (complete or partial). The prognostic value of Y chromosome deletion analysis in cases of oligozoospermia is important when one considers the progressive decrease of sperm number over time in men with AZFc deletions. Cryo-conservation of spermatozoa in these cases could avoid invasive techniques, such as TESE/ICSI, in the future. Male offspring that are conceived by ICSI or IVF techniques from father with oligozoospermia or azoospermia would also benefit from knowledge of their Y status, since the identification of the genetic defect will render future medical or surgical therapies unnecessary. Y microdeletion screening is therefore important, not only to define the aetiology of spermatogenic failure, but also because it gives precious information for a more appropriate clinical management of both the infertile male and his future male child.
Assuntos
Deleção de Genes , Cromossomo Y , Fatores Biológicos/genética , Humanos , Masculino , Oligospermia/genética , PrognósticoRESUMO
The aetiology of cryptorchidism is for the most part unknown and appears to be multifactorial. Recently, a product of Leydig cells termed Leydig insulin-like hormone (INSL3) has been proposed as a putative trophic hormone of the first part of descent. Absence of Insl3 in male mice results in bilateral cryptorchidism and mutations involving this gene may be a cause of cryptorchidism in man. We sequenced both exons of the human INSL3 gene in 31 men who presented with idiopathic unilateral or bilateral cryptorchidism. The only sequence variant was an amino acid substitution in the C-peptide of the molecule. This change was also found in a control group of normal fertile men indicating that it is a polymorphism unrelated to the phenotype. These results suggest that mutations involving the human INSL3 gene are not a common cause of cryptorchidism in man.
Assuntos
Criptorquidismo/genética , Mutação , Proteínas/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Inativação Gênica , Humanos , Insulina , Masculino , Dados de Sequência Molecular , Polimorfismo GenéticoRESUMO
Seventy-seven Ethiopians were investigated for mtDNA and Y chromosome-specific variations, in order to (1) define the different maternal and paternal components of the Ethiopian gene pool, (2) infer the origins of these maternal and paternal lineages and estimate their relative contributions, and (3) obtain information about ancient populations living in Ethiopia. The mtDNA was studied for the RFLPs relative to the six classical enzymes (HpaI, BamHI, HaeII, MspI, AvaII, and HincII) that identify the African haplogroup L and the Caucasoid haplogroups I and T. The sample was also examined at restriction sites that define the other Caucasoid haplogroups (H, U, V, W, X, J, and K) and for the simultaneous presence of the DdeI10394 and AluI10397 sites, which defines the Asian haplogroup M. Four polymorphic systems were examined on the Y chromosome: the TaqI/12f2 and the 49a,f RFLPs, the Y Alu polymorphic element (DYS287), and the sY81-A/G (DYS271) polymorphism. For comparison, the last two Y polymorphisms were also examined in 87 Senegalese previously classified for the two TaqI RFLPs. Results from these markers led to the hypothesis that the Ethiopian population (1) experienced Caucasoid gene flow mainly through males, (2) contains African components ascribable to Bantu migrations and to an in situ differentiation process from an ancestral African gene pool, and (3) exhibits some Y-chromosome affinities with the Tsumkwe San (a very ancient African group). Our finding of a high (20%) frequency of the "Asian" DdeI10394AluI10397 (++) mtDNA haplotype in Ethiopia is discussed in terms of the "out of Africa" model.
Assuntos
População Negra/genética , DNA Mitocondrial/genética , Etnicidade/genética , Polimorfismo Genético , Cromossomo Y , Mapeamento Cromossômico , Emigração e Imigração , Enzimas/genética , Etiópia , Pool Gênico , Marcadores Genéticos , Geografia , Haplótipos , Humanos , Masculino , Filogenia , Polimorfismo de Fragmento de Restrição , População Branca/genéticaRESUMO
The insulin like growth factor 4 (INSL4) gene belongs to the insulin gene superfamily and has been mapped by fluorescent in situ hybridization to 9p24. Expression of INSL4, of unknown function, has been recently detected in the perichondrium and ligaments of the human embryo. Here we have mapped INSL4 within the framework of a partial YAC contig covering the distal part of 9p to find out whether this gene lies within the critical region defined for the monosomy 9p syndrome. The gene was also located using a human-rodent radiation hybrid panel. INSL4 was found to be distal to the del(9p) critical region and excluded as a candidate for the syndrome. In addition, the positions of two relaxin genes (RLN1, RLN2) that belong to the same superfamily as INSL4 and which have also been mapped to chromosome 9, were refined. We have shown that the three genes are clustered in the same region.
Assuntos
Cromossomos Humanos Par 9 , Substâncias de Crescimento , Peptídeos e Proteínas de Sinalização Intercelular , Monossomia/genética , Proteínas da Gravidez/genética , Relaxina/genética , Animais , Mapeamento Cromossômico , Primers do DNA , Embrião de Mamíferos , Marcadores Genéticos , Humanos , Células Híbridas , Família Multigênica , Reação em Cadeia da Polimerase , Roedores , SíndromeRESUMO
In man, infertility is associated with microdeletions of specific regions of the long arm of the Y chromosome. This indicates that factors encoded by the Y chromosome are necessary for spermatogenesis. However, the majority of men with either idiopathic azoospermia or oligozoospermia have grossly intact Y chromosomes and the underlying causes of their infertility are unknown. We hypothesized that some of these individuals may carry other rearrangements or sequence variants on the non-recombining region of the Y chromosome that may be associated with reduced spermatogenesis. To test this hypothesis, we typed the Y chromosome in a group of Danish men with known sperm counts and compared the haplotype distribution with that of a group of unselected Danish males. We found that one class of Y chromosome, referred to as haplogroup 26+, was significantly overrepresented (27.9%; P < 0.001) in the group of men with either idiopathic oligozoospermia (defined as <20 x 10(6 )sperm/ml) or azoospermia compared to the control Danish male population (4.6%). This study defines, for the first time, a class of Y chromosome that is at risk for infertility in a European population. This observation suggests that selection may be indeed active on the Y chromosome, at least in the Danish population, raising the possibility that it could alter the pattern of Y chromosome haplotype distribution in the general population.
Assuntos
Haplótipos/genética , Contagem de Espermatozoides , Cromossomo Y/genética , Alelos , Evolução Molecular , Hormônio Foliculoestimulante/sangue , Marcadores Genéticos , Humanos , Infertilidade Masculina/genética , Inibinas/sangue , Hormônio Luteinizante/sangue , Masculino , Oligospermia/genética , Filogenia , Polimorfismo Genético , Sêmen/citologia , Globulina de Ligação a Hormônio Sexual/metabolismoRESUMO
Deletions of 9p have been associated with 46,XY gonadal dysgenesis, and the smallest region of overlap has been mapped to the tip of chromosome 9. Two candidate genes (DMRT1 and 2) have been found in the region. Despite intensive mutation searches, no mutations have been detected in these genes. To gain insights into the genomics of the region and to isolate other candidate genes for the phenotype, we have constructed a P1 artificial chromosome (PAC)/bacterial artificial chromosome (BAC) contig spanning over 500 kb and covering the consensus critical region. We have analyzed the expression pattern of several ESTs mapped or sublocalized within the framework of the contig. In addition, a sample shotgun sequencing of a PAC containing the mentioned DM genes led to the detection of novel transcripts displaying an expression pattern specific to testis and kidney, consistent with a role in the development of the urogenital system. One of them, expressed in adult testis and human embryos aged 4-5 weeks, encodes a potential polypeptide and is located immediately downstream of a sequence capable of encoding a novel DM domain. The region was partially screened for mutations in sex-reversed patients by Southern blot, sequencing, and FISH. No mutations were found. Our results suggest that the critical region on 9p involved in male-to-female sex reversal displays greater gene density and genomic complexity than previously anticipated. Future investigations will include functional and mutational studies of the novel transcripts mapped or sublocalized within the critical region by this study as well as cloning efforts to isolate additional candidate genes.
Assuntos
Cromossomos Humanos Par 9/genética , Proteínas de Ligação a DNA , Transtornos do Desenvolvimento Sexual/genética , Transcrição Gênica , Sistema Urogenital/metabolismo , Adulto , Deleção Cromossômica , Mapeamento Cromossômico , Mapeamento de Sequências Contíguas , Análise Mutacional de DNA , Embrião de Mamíferos , Etiquetas de Sequências Expressas , Feminino , Deleção de Genes , Testes Genéticos , Humanos , Mutação , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de DNA , Distribuição Tecidual , Fatores de Transcrição/genética , Cromossomo X , Cromossomo YRESUMO
The male to female ratio in autism is 4:1 in the global autistic population, but increases to 23:1 in autistic subjects without physical or brain abnormalities.(1) Despite this well-recognised gender difference, male predisposition to autistic disorder remains unexplained and the role of sex chromosomes is still debated. Numerical and structural abnormalities of the sex chromosomes are among the most frequently reported chromosomal disorders associated with autism. However, genome scans have failed to detect linkage on the X chromosome(2,3,4) and this approach cannot study the non-recombining region of the Y chromosome. In this study, we searched for a specific Y chromosome effect in autistic subjects. Using informative Y-polymorphic markers, the Y chromosome haplotypes of 111 autistic subjects from France, Sweden and Norway were defined and compared with relevant control populations. No significant difference in Y-haplotype distribution between the affected and control groups was observed. Although this study cannot exclude the presence of a Y susceptibility gene, our results are not suggestive of a Y chromosome effect in autism.