RESUMO
The human MSY ampliconic region is mainly composed of large duplicated sequences that are organized in eight palindromes (termed P1-P8), and may undergo arm-to-arm gene conversion. Although the importance of these elements is widely recognized, their evolutionary dynamics are still nuanced. Here, we focused on the P8 palindrome, which shows a complex evolutionary history, being involved in intra- and inter-chromosomal gene conversion. To disclose its evolutionary complexity, we performed a high-depth (50×) targeted next-generation sequencing of this element in 157 subjects belonging to the most divergent lineages of the Y chromosome tree. We found a total of 72 polymorphic paralogous sequence variants that have been exploited to identify 41 Y-Y gene conversion events that occurred during recent human history. Through our analysis, we were able to categorize P8 arms into three portions, whose molecular diversity was modelled by different evolutionary forces. Notably, the outer region of the palindrome is not involved in any gene conversion event and evolves exclusively through the action of mutational pressure. The inner region is affected by Y-Y gene conversion occurring at a rate of 1.52 × 10-5 conversions/base/year, with no bias towards the retention of the ancestral state of the sequence. In this portion, GC-biased gene conversion is counterbalanced by a mutational bias towards AT bases. Finally, the middle region of the arms, in addition to intra-chromosomal gene conversion, is involved in X-to-Y gene conversion (at a rate of 6.013 × 10-8 conversions/base/year) thus being a major force in the evolution of the VCY/VCX gene family.
Assuntos
Cromossomos Humanos Y , Conversão Gênica , Humanos , Conversão Gênica/genética , Cromossomos Humanos Y/genética , Mutação , Evolução MolecularRESUMO
About one-quarter of the euchromatic portion of the male-specific region of the human Y chromosome consists of large duplicated sequences that are organized in eight palindromes (termed P1-P8), which undergo arm-to arm gene conversion, a proposed mechanism for maintaining their sequence integrity. Although the relevance of gene conversion in the evolution of palindromic sequences has been profoundly recognized, the dynamic of this mechanism is still nuanced. To shed light into the evolution of these genomic elements, we performed a high-depth (50×) targeted next-generation sequencing of the palindrome P6 in 157 subjects belonging to the most divergent evolutionary lineages of the Y chromosome. We found 118 new paralogous sequence variants, which were placed into the context of a robust Y chromosome phylogeny based on 7240 SNPs of the X-degenerate region. We mapped along the phylogeny 80 gene conversion events that shaped the diversity of P6 arms during recent human history. In contrast to previous studies, we demonstrated that arm-to-arm gene conversion, which occurs at a rate of 6.01 × 10 -6 conversions/base/year, is not biased toward the retention of the ancestral state of sequences. We also found a significantly lower mutation rate of the arms (6.18 × 10-10 mutations/base/year) compared with the spacer (9.16 × 10-10 mutations/base/year), a finding that may explain the observed higher inter-species conservation of arms, without invoking any bias of conversion. Finally, by formally testing the mutation/conversion balance in P6, we found that the arms of this palindrome reached a steady-state equilibrium between mutation and gene conversion.
Assuntos
Cromossomos Humanos Y , Evolução Molecular , Conversão Gênica , Sequências Repetidas Invertidas , Mutação , Mapeamento Cromossômico , Variação Genética , Humanos , Masculino , Taxa de Mutação , FilogeniaRESUMO
Throughout the past few years, a lively debate emerged about the timing and magnitude of the human migrations between the Iberian Peninsula and the Maghreb. Several pieces of evidence, including archaeological, anthropological, historical, and genetic data, have pointed to a complex and intermingled evolutionary history in the western Mediterranean area. To study to what extent connections across the Strait of Gibraltar and surrounding areas have shaped the present-day genomic diversity of its populations, we have performed a screening of 2.5 million single-nucleotide polymorphisms in 142 samples from southern Spain, southern Portugal, and Morocco. We built comprehensive data sets of the studied area and we implemented multistep bioinformatic approaches to assess population structure, demographic histories, and admixture dynamics. Both local and global ancestry inference showed an internal substructure in the Iberian Peninsula, mainly linked to a differential African ancestry. Western Iberia, from southern Portugal to Galicia, constituted an independent cluster within Iberia characterized by an enriched African genomic input. Migration time modeling showed recent historic dates for the admixture events occurring both in Iberia and in the North of Africa. However, an integrative vision of both paleogenomic and modern DNA data allowed us to detect chronological transitions and population turnovers that could be the result of transcontinental migrations dating back from Neolithic times. The present contribution aimed to fill the gaps in the modern human genomic record of a key geographic area, where the Mediterranean and the Atlantic come together.
Assuntos
Variação Genética , Genoma Humano , Migração Humana , África do Norte , Humanos , Região do Mediterrâneo , Filogeografia , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Analyses of the genomic variation in the western Mediterranean population are being used to reveal its evolutionary history and to understand the molecular basis of particular diseases. AIM: To observe the ß-thalassemia mutational spectrum in western Andalusia, Spain, in the context of the Mediterranean. In addition, associations between disease and neutral gene variants within the ß-globin gene (HBB) were also evaluated. SUBJECTS AND METHODS: This study included 63 unrelated individuals diagnosed with ß-thalassemia. In addition, 97 unrelated, healthy subjects of the same territory were also analysed as proxies of the normal genetic background. Allele associations and population genetic structure analyses were performed using different methodologies. RESULTS: Data have revealed a rather restricted spectrum of ß-thalassemia mutations in the analysed sample. Although the detected variants fit well with the Mediterranean pattern, certain singularities support a structure of some specific ß-thalassemia alleles. The IVSI-1 (G > A) shows a strong regionalisation. The spatial correlogram revealed a typically narrow wave structure, presumably linked to genetic isolation and genetic drift. CONCLUSIONS: The long history of endemic malaria in the study territory, the rather high consanguinity rates among its autochthonous population, and other demographic features have been used here to understand the western Andalusian ß-thalassemia molecular portrait.
Assuntos
Talassemia beta , Alelos , Humanos , Mutação , Espanha/epidemiologia , Globinas beta/genética , Talassemia beta/epidemiologia , Talassemia beta/genéticaRESUMO
OBJECTIVES: The 3' regulatory region of the immunoglobulin heavy chain gene (IGH) includes the HS1.2 enhancer displaying length polymorphism with four known variants. The goal of the research was to provide an overview of this variability and of its evolutionary significance across human populations. MATERIALS AND METHODS: We compiled published and original data on HS1.2 polymorphism in 3,100 subjects from 26 human populations. Moreover, we imputed the haplotypic arrangement of the HS1.2 region in the 1000 Genomes Project (1KGP). In this dataset, imputation could also be obtained for the G1m-G3m allotype by virtue of the precise correspondence between serological types and amino acid (and DNA) substitutions in IGHG1 and IGHG3. RESULTS: HS1.2 variant frequencies displayed similar patterns of continental partitioning as those reported in the literature for the physically neighboring IGHG1-IGHG3 system. The 1KGP data revealed that linkage disequilibrium (LD) can explain the spread of joint HS1.2-IGHG1-IGHG3 associations across continents and within continental populations, with stronger LD out of Africa and the features of an evolutionarily stable genomic block with differential expression in lymphoblastoid cell lines. DISCUSSION: Strong population structuring involves at least the entire 70 kb genomic region here considered, due to the tight LD which maintained HS1.2, IGHG1, and IGHG3 in nonrandom arrangements. This might be key to better understand the evolutionary path of the entire genomic region driven by immune response capabilities, during the formation of continental gene pools.
Assuntos
Cadeias Pesadas de Imunoglobulinas/genética , Desequilíbrio de Ligação , Polimorfismo Genético , Grupos Raciais/genética , Feminino , Haplótipos , Humanos , Alótipos Gm de Imunoglobulina/genética , MasculinoRESUMO
BACKGROUND: The geography of southern Iberia and an abundant archaeological record of human occupation are ideal conditions for a full understanding of scenarios of genetic history in the area. Recent advances in the phylogeography of Y-chromosome lineages offer the opportunity to set upper bounds for the appearance of different genetic components. AIM: To provide a global knowledge on the Y haplogroups observed in Andalusia with their Y microsatellite variation. Preferential attention is given to the vehement debate about the age, origin and expansion of R1b-M269 clade and sub-lineages. SUBJECT AND METHODS: Four hundred and fourteen male DNA samples from western and eastern autochthonous Andalusians were genotyped for a set of Y-SNPs and Y-STRs. Gene diversity, potential population genetic structures and coalescent times were assessed. RESULTS: Most of the analysed samples belong to the European haplogroup R1b1a1a2-M269, whereas haplogroups E, J, I, G and T show lower frequencies. A phylogenetic dissection of the R1b-M269 was performed and younger time frames than those previously reported in the literature were obtained for its sub-lineages. CONCLUSION: The particular Andalusian R1b-M269 assemblage confirms the shallow topology of the clade. Moreover, the sharing of lineages with the rest of Europe indicates the impact in Iberia of an amount of pre-existing diversity, with the possible exception of R1b-DF27. Lineages such as J2-M172 and G-M201 highlight the importance of maritime travels of early farmers who reached the Iberian Peninsula.
Assuntos
Cromossomos Humanos Y/genética , Fluxo Gênico , Migração Humana , Humanos , Masculino , Repetições de Microssatélites , Filogenia , Filogeografia , EspanhaRESUMO
OBJECTIVES: This work aimed to describe the genetic landscape of the Balkan Peninsula, as revealed by STR markers commonly used in forensics and spatial methods specifically developed for genetic data. METHODS: We generated and analyzed 16 short tandem repeats (STRs) autosomal genotypes in 287 subjects from ten administrative/geographical regions of Eastern Europe (Romania and the Republic of Moldova). We report estimates of the allele frequencies in these sub-populations, their fixation indexes, and use these results to complement previous spatial analyses of Southern Europe. RESULTS: In seven out of ten analyzed regional samples the heterozygosity, averaged across loci, was lower than expected. The average Fis was 0.011. Among the 16 loci, five returned a significant fixation index Fst. The composite Fst across the 16 loci, among the 10 regional samples, was 0.00417, a figure twice as large as that obtained with the same markers across the entire Northern Mediterranean. The first spatial principal component (sPC1) returned the picture of a Central-European pattern of frequencies for the Carpathians, which extended to the Southern boundary of the Balkan Peninsula. However, the 8 alleles extracted by sPC1 returned a picture of a strong reduction of the migration rate in the Carpathian region, mostly between the inner locations. CONCLUSIONS: Our results revealed an unexpected heterogeneity in the area. We believe that populations from some regions will require treatment as distinct entities when considered in forensic applications.
Assuntos
Frequência do Gene , Variação Genética , Repetições de Microssatélites , Genótipo , Humanos , Moldávia , RomêniaRESUMO
BACKGROUND: Tetranucleotide Short Tandem Repeats (STRs) for human identification and common use in forensic cases have recently been used to address the population genetics of the North-Eastern Mediterranean area. However, to gain confidence in the inferences made using STRs, this kind of analysis should be challenged with changes in three main aspects of the data, i.e. the sizes of the samples, their distance across space and the genetic background from which they are drawn. AIM: To test the resilience of the gradients previously detected in the North-Eastern Mediterranean to the enlargement of the surveyed area and population set, using revised data. SUBJECTS AND METHODS: STR genotype profiles were obtained from a publicly available database (PopAffilietor databank) and a dataset was assembled including >7000 subjects from the Arabian Peninsula to Scandinavia, genotyped at eight loci. Spatial principal component analysis (sPCA) was applied and the frequency maps of the nine alleles which contributed most strongly to sPC1 were examined in detail. RESULTS: By far the greatest part of diversity was summarised by a single spatial principal component (sPC1), oriented along a SouthEast-to-NorthWest axis. The alleles with the top 5% squared loadings were TH01(9.3), D19S433(14), TH01(6), D19S433(15.2), FGA(20), FGA(24), D3S1358(14), FGA(21) and D2S1338(19). These results confirm a clinal pattern over the whole range for at least four loci (TH01, D19S433, FGA, D3S1358). CONCLUSIONS: Four of the eight STR loci (or even alleles) considered here can reproducibly capture continental arrangements of diversity. This would, in principle, allow for the exploitation of forensic data to clarify important aspects in the formation of local gene pools.
Assuntos
Frequência do Gene , Variação Genética , Genótipo , Repetições de Microssatélites , África do Norte , Genética Populacional , Região do Mediterrâneo , Oriente MédioRESUMO
Sequence diversity and the ages of the deepest nodes of the MSY phylogeny remain largely unexplored due to the severely biased collection of SNPs available for study. We characterized 68 worldwide Y chromosomes by high-coverage next-generation sequencing, including 18 deep-rooting ones, and identified 2386 SNPs, 80% of which were novel. Many aspects of this pool of variants resembled the pattern observed among genome-wide de novo events, suggesting that in the MSY, a large proportion of newly arisen alleles has survived in the phylogeny. Some degree of purifying selection emerged in the form of an excess of private missense variants. Our tree recapitulated the previously known topology, but the relative lengths of major branches were drastically modified and the associated node ages were remarkably older. We found significantly different branch lengths when comparing the rare deep-rooted A1b African lineage with the rest of the tree. Our dating results and phylogeography led to the following main conclusions: (1) Patrilineal lineages with ages approaching those of early AMH fossils survive today only in central-western Africa; (2) only a few evolutionarily successful MSY lineages survived between 160 and 115 kya; and (3) an early exit out of Africa (before 70 kya), which fits recent western Asian archaeological evidence, should be considered. Our experimental design produced an unbiased resource of new MSY markers informative for the initial formation of the anatomically modern human gene pool, i.e., a period of our evolution that had been previously considered to be poorly accessible with paternally inherited markers.
Assuntos
População Negra/genética , Cromossomos Humanos Y/genética , Polimorfismo de Nucleotídeo Único/genética , Cromossomos Humanos Y/classificação , Evolução Molecular , Variação Genética , Genoma Humano , Humanos , Taxa de Mutação , Mutação de Sentido Incorreto , Filogenia , Seleção Genética , Análise de Sequência de DNARESUMO
BACKGROUND: The structure of haplogroup H reveals significant differences between the western and eastern edges of the Mediterranean, as well as between the northern and southern regions. Human populations along the westernmost Mediterranean coasts, which were settled by individuals from two continents separated by a relatively narrow body of water, show the highest frequencies of mitochondrial haplogroup H. These characteristics permit the analysis of ancient migrations between both shores, which may have occurred via primitive sea crafts and early seafaring. We collected a sample of 750 autochthonous people from the southern Iberian Peninsula (Andalusians from Huelva and Granada provinces). We performed a high-resolution analysis of haplogroup H by control region sequencing and coding SNP screening of the 337 individuals harboring this maternal marker. Our results were compared with those of a wide panel of populations, including individuals from Iberia, the Maghreb, and other regions around the Mediterranean, collected from the literature. RESULTS: Both Andalusian subpopulations showed a typical western European profile for the internal composition of clade H, but eastern Andalusians from Granada also revealed interesting traces from the eastern Mediterranean. The basal nodes of the most frequent H sub-haplogroups, H1 and H3, harbored many individuals of Iberian and Maghrebian origins. Derived haplotypes were found in both regions; haplotypes were shared far more frequently between Andalusia and Morocco than between Andalusia and the rest of the Maghreb. These and previous results indicate intense, ancient and sustained contact among populations on both sides of the Mediterranean. CONCLUSIONS: Our genetic data on mtDNA diversity, combined with corresponding archaeological similarities, provide support for arguments favoring prehistoric bonds with a genetic legacy traceable in extant populations. Furthermore, the results presented here indicate that the Strait of Gibraltar and the adjacent Alboran Sea, which have often been assumed to be an insurmountable geographic barrier in prehistory, served as a frequently traveled route between continents.
Assuntos
DNA Mitocondrial/genética , Genética Populacional , Haplótipos , Migração Humana , Europa (Continente) , Evolução Molecular , Fluxo Gênico , Variação Genética , Humanos , Região do Mediterrâneo , Grupos RaciaisRESUMO
BACKGROUND: Today, African pastoralists are found mainly in the Sahel/Savannah belt spanning 6,000 km from west to east, flanked by the Sahara to the north and tropical rainforests to the south. The most significant group among them are the Fulani who not only keep cattle breeds of possible West Eurasian ancestry, but form themselves a gene pool containing some paternally and maternally-transmitted West Eurasian haplogroups. MATERIALS AND METHODS: We generated complete sequences for 33 mitogenomes belonging to haplogroups H1 and U5 (23 and 10, respectively), and genotyped 16 STRs in 65 Y chromosomes belonging to haplogroup R1b-V88. RESULTS: We show that age estimates of the maternal lineage H1cb1, occurring almost exclusively in the Fulani, point to the time when the first cattle herders settled the Sahel/Savannah belt. Similar age estimates were obtained for paternal lineage R1b-V88, which occurs today in the Fulani but also in other, mostly pastoral populations. Maternal clade U5b1b1b, reported earlier in the Berbers, shows a shallower age, suggesting another possibly independent input into the Sahelian pastoralist gene pool. CONCLUSIONS: Despite the fact that animal domestication originated in the Near East â¼ 10 ka, and that it was from there that animals such as sheep, goats as well as cattle were introduced into Northeast Africa soon thereafter, contemporary cattle keepers in the Sahel/Savannah belt show uniparental genetic affinities that suggest the possibility of an ancient contact with an additional ancestral population of western Mediterranean ancestry.
Assuntos
Agricultura/história , População Negra/genética , DNA Mitocondrial/genética , Haplótipos/genética , Migração Humana/história , África Subsaariana , Antropologia Física , Cromossomos Humanos Y/genética , Genética Populacional , História Antiga , Humanos , Masculino , FilogeniaRESUMO
Many studies of human populations have used the male-specific region of the Y chromosome (MSY) as a marker, but MSY sequence variants have traditionally been subject to ascertainment bias. Also, dating of haplogroups has relied on Y-specific short tandem repeats (STRs), involving problems of mutation rate choice, and possible long-term mutation saturation. Next-generation sequencing can ascertain single nucleotide polymorphisms (SNPs) in an unbiased way, leading to phylogenies in which branch-lengths are proportional to time, and allowing the times-to-most-recent-common-ancestor (TMRCAs) of nodes to be estimated directly. Here we describe the sequencing of 3.7 Mb of MSY in each of 448 human males at a mean coverage of 51×, yielding 13,261 high-confidence SNPs, 65.9% of which are previously unreported. The resulting phylogeny covers the majority of the known clades, provides date estimates of nodes, and constitutes a robust evolutionary framework for analyzing the history of other classes of mutation. Different clades within the tree show subtle but significant differences in branch lengths to the root. We also apply a set of 23 Y-STRs to the same samples, allowing SNP- and STR-based diversity and TMRCA estimates to be systematically compared. Ongoing purifying selection is suggested by our analysis of the phylogenetic distribution of nonsynonymous variants in 15 MSY single-copy genes.
Assuntos
Cromossomos Humanos Y/genética , Polimorfismo de Nucleotídeo Único/genética , Evolução Molecular , Projeto HapMap , Humanos , Masculino , Filogenia , Análise de Sequência de DNARESUMO
Age at the onset of motor symptoms in Huntington disease (HD) is determined largely by the length of a CAG repeat expansion in HTT but is also influenced by other genetic factors. We tested whether common genetic variation near the mutation site is associated with differences in the distribution of expanded CAG alleles or age at the onset of motor symptoms. To define disease-associated single-nucleotide polymorphisms (SNPs), we compared 4p16.3 SNPs in HD subjects with population controls in a case:control strategy, which revealed that the strongest signals occurred at a great distance from the HD mutation as a result of "synthetic association" with SNP alleles that are of low frequency in population controls. Detailed analysis delineated a prominent ancestral haplotype that accounted for â¼50% of HD chromosomes and extended to at least 938 kb on about half of these. Together, the seven most abundant haplotypes accounted for â¼83% of HD chromosomes. Neither the extended shared haplotype nor the individual local HTT haplotypes were associated with altered CAG-repeat length distribution or residual age at the onset of motor symptoms, arguing against modification of these disease features by common cis-regulatory elements. Similarly, the 11 most frequent control haplotypes showed no trans-modifier effect on age at the onset of motor symptoms. Our results argue against common local regulatory variation as a factor influencing HD pathogenesis, suggesting that genetic modifiers be sought elsewhere in the genome. They also indicate that genome-wide association analysis with a small number of cases can be effective for regional localization of genetic defects, even when a founder effect accounts for only a fraction of the disorder.
Assuntos
Cromossomos Humanos Par 4 , Doença de Huntington/genética , Idade de Início , Alelos , Estudos de Casos e Controles , Efeito Fundador , Estudo de Associação Genômica Ampla/métodos , Haplótipos , Humanos , Mutação , Polimorfismo de Nucleotídeo Único , Repetições de TrinucleotídeosRESUMO
To clarify the population history of dentatorubropallidoluysian atrophy (DRPLA) in Italy and to date back the introduction of the mutation, we reconstructed extended haplotypes flanking the CAG repeat in 10 patients of Italian ancestry, analyzing their similarity/dissimilarity as a function of distance from the CAG repeat. Our aim was to compare the hypothesis of a single, recent genealogy connecting all the observed haplotypes with the alternative hypothesis of multiple introductions by more distantly related haplotypes from outer sources. Polymorphic DNA markers were chosen to cover a region of 153 kb flanking the CAG repeat, that is, informative for dating the age of the DNA segment unaffected by recombination. In all patients, an expansion of the ATN1 CAG segment was confirmed residing onto the same narrow haplotype described to be associated with the CAG expansion in the Japanese and Portuguese populations. We also observed the disruption of the DRPLA haplotype at longer distances, on both sides of the CAG. Our results are compatible with a single founder in the last 600 years, most likely before the last 270 years. These estimates for the Sicilian population largely overlap a period in which the Japanese haplotype with the DRPLA mutation could have been introduced by the Portuguese maritime travelers.
Assuntos
Haplótipos/genética , Mutação/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Atrofia , Pareamento de Bases/genética , Feminino , Humanos , Itália , Masculino , Linhagem , Recombinação Genética/genéticaRESUMO
BACKGROUND: The archeology and history of the ancient Mediterranean have shown that this sea has been a permeable obstacle to human migration. Multiple cultural exchanges around the Mediterranean have taken place with presumably population admixtures. A gravitational territory of those migrations has been the Iberian Peninsula. Here we present a comprehensive analysis of the maternal gene pool, by means of control region sequencing and PCR-RFLP typing, of autochthonous Andalusians originating from the coastal provinces of Huelva and Granada, located respectively in the west and the east of the region. RESULTS: The mtDNA haplogroup composition of these two southern Spanish populations has revealed a wide spectrum of haplogroups from different geographical origins. The registered frequencies of Eurasian markers, together with the high incidence and diversification of African maternal lineages (15% of the total mitochondrial variability) among Huelva Andalusians when compared to its eastwards relatives of Granada and other Iberian populations, constitute relevant findings unknown up-to-date on the characteristics of mtDNA within Andalusia that testifies a female population substructure. Therefore, Andalusia must not be considered a single, unique population. CONCLUSIONS: The maternal legacy among Andalusians reflects distinctive local histories, pointing out the role of the westernmost territory of Peninsular Spain as a noticeable recipient of multiple and diverse human migrations. The obtained results underline the necessity of further research on genetic relationships in both sides of the western Mediterranean, using carefully collected samples from autochthonous individuals. Many studies have focused on recent North African gene flow towards Iberia, yet scientific attention should be now directed to thoroughly study the introduction of European genes in northwest Africa across the sea, in order to determine its magnitude, timescale and methods, and to compare them to those terrestrial movements from eastern Africa and southwestern Asia.
Assuntos
DNA Mitocondrial/genética , Genética Populacional , Haplótipos , Evolução Molecular , Fluxo Gênico , Pool Gênico , Migração Humana , Humanos , Modelos Genéticos , EspanhaRESUMO
BACKGROUND: The APOE gene has received much attention due to the remarkable spatial variation patterns of some of its genotypes and alleles in human populations and to its relevance in biomedicine. AIM: This work was addressed to investigate the extent of APOE polymorphism between autochthonous Andalusians originating from Huelva and Granada provinces. No data on this marker in these southern Spanish coastal populations are available up to date. SUBJECTS AND METHODS: This study used genomic DNA from healthy, unrelated Andalusians of both sexes (n = 322). All samples were genotyped for two SNPs, rs429358 and rs7412, which determine the three APOE alleles: ε2, ε3 and ε4. For analyses, a TaqMan-based technique was applied using a RT-PCR. Comparisons with other Mediterranean populations were performed based on multivariate analysis. RESULTS: A relatively high frequency of ε4 in Granada (eastern Andalusia), as well as a low ε2 frequency in Huelva (western Andalusia) were observed. The finding that ε4 allele in Southern Spain and Portugal is higher than expected given its geographical location poses an interesting question for this study, given the well-established APOE-ε4 gradient in Europe. CONCLUSION: This population study may represent useful information for further prospective anthropological and molecular genetic studies focused on unravelling the relationship between population genetic composition and specific human diseases.
Assuntos
Apolipoproteínas E/genética , Frequência do Gene , Polimorfismo de Nucleotídeo Único , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase em Tempo Real , EspanhaRESUMO
We analyzed the structure of human long non-coding RNA (lncRNAs) genes to investigate whether the non-coding transcriptome is organized in modular domains, as is the case for protein-coding genes. To this aim, we compared all known human lncRNA exons and identified 340 pairs of exons with high sequence and/or secondary structure similarity but embedded in a dissimilar sequence context. We grouped these pairs in 106 clusters based on their reciprocal similarities. These shared modules are highly conserved between humans and the four great ape species, display evidence of purifying selection and likely arose as a result of recent segmental duplications. Our analysis contributes to the understanding of the mechanisms driving the evolution of the non-coding genome and suggests additional strategies towards deciphering the functional complexity of this class of molecules.
RESUMO
In humans, the HS1.2 enhancer in the Ig heavy-chain locus is modular, with length polymorphism. Previous studies have shown the following features for this variation: (i) strong population structuring; (ii) association with autoimmune diseases; and (iii) association with developmental changes in Ig expression. The HS1.2 region could then be considered as a contributor to inter-individual diversity in humoral response in adaptive immunity. We experimentally determined the HS1.2-length class genotype in 72 of the 1000 Genomes CEU cell lines and assigned the HS1.2 alleles to haplotypes defined by 18 landmark SNPs. We also sequenced the variable portion and ~200 bp of the flanking DNA of 34 HS1.2 alleles. Furthermore, we computationally explored the ability of different allelic arrangements to bind transcription factors. Non-random association between HS1.2 and Gm allotypes in the European population clearly emerged. We show a wealth of variation in the modular composition of HS1.2, with five SNPs further contributing to diversity. Longer alleles offer more potential sites for binding but, for same-length alleles, SNP variation creates/destroys potential binding sites. Altogether, the arrangements of modules and SNP alleles both inside and outside HS1.2 denote an organization of diversity far from randomness. In the context of the strong divergence of human populations for this genomic region and the reported disease associations, our results suggest that selective forces shaped the pattern of its diversity.
Assuntos
Elementos Facilitadores Genéticos , Polimorfismo de Nucleotídeo Único , Humanos , Elementos Facilitadores Genéticos/genética , Alelos , Haplótipos , Genoma Humano , Fatores de Transcrição/genética , Sítios de LigaçãoRESUMO
Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. It is caused by the expansion of the HTT CAG repeat, which is the major determinant of age at onset (AO) of motor symptoms. Aberrant function of N-methyl-D-aspartate receptors and/or overexposure to dopamine has been suggested to cause significant neurotoxicity, contributing to HD pathogenesis. We used genetic association analysis in 1,628 HD patients to evaluate candidate polymorphisms in N-methyl-D-aspartate receptor subtype genes (GRIN2A rs4998386 and rs2650427, and GRIN2B rs1806201) and functional polymorphisms in genes in the dopamine pathway (DAT1 3' UTR 40-bp variable number tandem repeat (VNTR), DRD4 exon 3 48-bp VNTR, DRD2 rs1800497, and COMT rs4608) as potential modifiers of the disease process. None of the seven polymorphisms tested was found to be associated with significant modification of motor AO, either in a dominant or additive model, after adjusting for ancestry. The results of this candidate-genetic study therefore do not provide strong evidence to support a modulatory role for these variations within glutamatergic and dopaminergic genes in the AO of HD motor manifestations.
Assuntos
Doença de Huntington/genética , Polimorfismo Genético , Receptores Dopaminérgicos/genética , Receptores de N-Metil-D-Aspartato/genética , Idade de Início , Catecol O-Metiltransferase/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Estudos de Associação Genética , Humanos , Doença de Huntington/epidemiologia , Vias Neurais/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D4/genéticaRESUMO
The African Sahel is conducive to studies of divergence/admixture genetic events as a result of its population history being so closely related with past climatic changes. Today, it is a place of the co-existence of two differing food-producing subsistence systems, i.e., that of sedentary farmers and nomadic pastoralists, whose populations have likely been formed from several dispersed indigenous hunter-gatherer groups. Using new methodology, we show here that the male gene pool of the extant populations of the African Sahel harbors signatures of multiple and differentiated contributions from different genetic sources. We also show that even if the Fulani pastoralists and their neighboring farmers share high frequencies of four Y chromosome subhaplogroups of E, they have drawn on molecularly differentiated subgroups at different times. These findings, based on combinations of SNP and STR polymorphisms, add to our previous knowledge and highlight the role of differences in the demographic history and displacements of the Sahelian populations as a major factor in the segregation of the Y chromosome lineages in Africa. Interestingly, within the Fulani pastoralist population as a whole, a differentiation of the groups from Niger is characterized by their high presence of R1b-M343 and E1b1b1-M35. Moreover, the R1b-M343 is represented in our dataset exclusively in the Fulani group and our analyses infer a north-to-south African migration route during a recent past.