Daniele Sellitto

Tracing European Founder Lineages in the Near Eastern mtDNA Pool

Founder analysis is a method for analysis of nonrecombining DNA sequence data, with the aim of identification and dating of migrations into new territory. The method picks out founder sequence types in potential source populations and dates lineage clusters deriving from them in the settlement zone of interest. Here, using mtDNA, we apply the approach to the colonization of Europe, to estimate the proportion of modern lineages whose ancestors arrived during each major phase of settlement. To estimate the Palaeolithic and Neolithic contributions to European mtDNA diversity more accurately than was previously achievable, we have now extended the Near Eastern, European, and northern-Caucasus databases to 1,234, 2, 804, and 208 samples, respectively. Both back-migration into the source population and recurrent mutation in the source and derived populations represent major obstacles to this approach. We have developed phylogenetic criteria to take account of both these factors, and we suggest a way to account for multiple dispersals of common sequence types. We conclude that (i) there has been substantial back-migration into the Near East, (ii) the majority of extant mtDNA lineages entered Europe in several waves during the Upper Palaeolithic, (iii) there was a founder effect or bottleneck associated with the Last Glacial Maximum, 20,000 years ago, from which derives the largest fraction of surviving lineages, and (iv) the immigrant Neolithic component is likely to comprise less than one-quarter of the mtDNA pool of modern Europeans.

Phylogeographic analysis of haplogroup E3b (E-M215) y chromosomes reveals multiple migratory events within and out of Africa.

We explored the phylogeography of human Y-chromosomal haplogroup E3b by analyzing 3401 individuals from five continents. Our data refine the phylogeny of the entire haplogroup, which appears as a collection of lineages with very different evolutionary histories, and reveal signatures of several distinct processes of migrations and/or recurrent gene flow that occurred in Africa and western Eurasia over the past 25000 years. In Europe, the overall frequency pattern of haplogroup E-M78 does not support the hypothesis of a uniform spread of people from a single parental Near Eastern population. The distribution of E-M81 chromosomes in Africa closely matches the present area of distribution of Berber-speaking populations on the continent, suggesting a close haplogroup-ethnic group parallelism. E-M34 chromosomes were more likely introduced in Ethiopia from the Near East. In conclusion, the present study shows that earlier work based on fewer Y-chromosome markers led to rather simple historical interpretations and highlights the fact that many population-genetic analyses are not robust to a poorly resolved phylogeny.

Do the four clades of the mtDNA haplogroup L2 evolve at different rates

Forty-seven mtDNAs collected in the Dominican Republic and belonging to the African-specific haplogroup L2 were studied by high-resolution RFLP and control-region sequence analyses. Four sets of diagnostic markers that subdivide L2 into four clades (L2a-L2d) were identified, and a survey of published African data sets appears to indicate that these clades encompass all L2 mtDNAs and harbor very different geographic/ethnic distributions. One mtDNA from each of the four clades was completely sequenced by means of a new sequencing protocol that minimizes time and expense. The phylogeny of the L2 complete sequences showed that the two mtDNAs from L2b and L2d seem disproportionately derived, compared with those from L2a and L2c. This result is not consistent with a simple model of neutral evolution with a uniform molecular clock. The pattern of nonsynonymous versus synonymous substitutions hints at a role for selection in the evolution of human mtDNA. Regardless of whether selection is shaping the evolution of modern human mtDNAs, the population screening of L2 mtDNAs for the mutations identified by our complete sequence study should allow the identification of marker motifs of younger age with more restricted geographic distributions, thus providing new clues about African prehistory and the origin and relationships of African ethnic groups.

The A1555G Mutation in the 12S rRNA Gene of Human mtDNA: Recurrent Origins and Founder Events in Families Affected by Sensorineural Deafness

The mtDNA variation of 50 Spanish and 4 Cuban families affected by nonsyndromic sensorineural deafness due to the A1555G mutation in the 12S rRNA gene was studied by high-resolution RFLP analysis and sequencing of the control region. Phylogenetic analyses of haplotypes and detailed survey of population controls revealed that the A1555G mutation can be attributed to >/=30 independent mutational events among the 50 Spanish families and that it occurs on mtDNA haplogroups that are common in all European populations. This indicates that the relatively high detection rate of this mutation in Spain is not due to sampling biases or to a single major founder event. Moreover, the distribution of these mutational events on different haplogroups is compatible with a random occurrence of the A1555G mutation and tends to support the conclusion that mtDNA backgrounds do not play a significant role in the expression of the mutation. Overall, these findings appear to indicate that the rare detection of this mutation in other populations is most likely due to inadequacy in patient ascertainment and molecular screening. This probable lack of identification of the A1555G mutation in subjects affected by sensorineural hearing loss implies that their maternally related relatives are not benefiting from presymptomatic detection and information concerning their increased risk of ototoxicity due to aminoglycoside treatments.

Human Y chromosome haplogroup R-V88: a paternal genetic record of early mid Holocene trans-Saharan connections and the spread of Chadic languages

Although human Y chromosomes belonging to haplogroup R1b are quite rare in Africa, being found mainly in Asia and Europe, a group of chromosomes within the paragroup R-P25* are found concentrated in the central-western part of the African continent, where they can be detected at frequencies as high as 95%. Phylogenetic evidence and coalescence time estimates suggest that R-P25* chromosomes (or their phylogenetic ancestor) may have been carried to Africa by an Asia-to-Africa back migration in prehistoric times. Here, we describe six new mutations that define the relationships among the African R-P25* Y chromosomes and between these African chromosomes and earlier reported R-P25 Eurasian sub-lineages. The incorporation of these new mutations into a phylogeny of the R1b haplogroup led to the identification of a new clade (R1b1a or R-V88) encompassing all the African R-P25* and about half of the few European/west Asian R-P25* chromosomes. A worldwide phylogeographic analysis of the R1b haplogroup provided strong support to the Asia-to-Africa back-migration hypothesis. The analysis of the distribution of the R-V88 haplogroup in >1800 males from 69 African populations revealed a striking genetic contiguity between the Chadic-speaking peoples from the central Sahel and several other Afroasiatic-speaking groups from North Africa. The R-V88 coalescence time was estimated at 9200–5600 kya, in the early mid Holocene. We suggest that R-V88 is a paternal genetic record of the proposed mid-Holocene migration of proto-Chadic Afroasiatic speakers through the Central Sahara into the Lake Chad Basin, and geomorphological evidence is consistent with this view.

Mitochondrial DNA Haplogroups Do Not Play a Role in the Variable Phenotypic Presentation of the A3243G Mutation

Thirty-five mitochondrial (mt) DNAs from Spain that harbor the mutation A3243G in association with either MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) syndrome or a wide array of disease phenotypes (ranging from diabetes and deafness to a mixture of chronic progressive external ophthalmoplegic symptoms and strokelike episodes) were studied by use of high-resolution restriction fragment length polymorphism analysis and control-region sequencing. A total of 34 different haplotypes were found, indicating that all instances of the A3243G mutation are probably due to independent mutational events. Haplotypes were distributed into 13 haplogroups whose frequencies were close to those of the general Spanish population. Moreover, there was no statistically significant difference in haplogroup distribution between patients with MELAS and those with disease phenotypes other than MELAS. Overall, these data indicate that the A3243G mutation harbors all the evolutionary features expected from a severely deleterious mtDNA mutation under strong negative selection, and they reveal that European mtDNA backgrounds do not play a substantial role in modulating the mutations phenotypic expression.

Realidad social de los pacientes con isquemia crítica de miembros inferiores

Realidad social de los pacientes con isquemia critica de miembros inferiores Resumen. Objetivo. Realizar una aproximacion a la realidad social de los pacientes que alcanzan los estadios mas avanzados de isquemia cronica de miembros inferiores (MMII) (isquemia critica). Pacientes y metodos. Se registran mediante entrevista a paciente y familiar, datos relacionados con la vivienda habitual, entorno sociofamiliar, recursos economicos y nivel de instruccion de 50 pacientes ingresados en nuestro servicio con el diagnostico de isquemia critica de MMII, entre el 1 de octubre y el 31 de diciembre de 2005. Se realiza una comparacion posterior con los mismos datos de la Encuesta de condiciones de vida del Instituto Nacional de Estadistica (INE) correspondiente a la zona estudiada y al mismo grupo de edad. Resultados. La media de edad de los pacientes es de 69,1 anos, siendo el 84% hombres y el 16% mujeres. Se constata una tasa de pobreza relativa del 50% en los pacientes con isquemia critica frente al 24,8% en la poblacion local correspondiente a la edad. El 26% de los pacientes estudiados son analfabetos, frente al 11,5% de la poblacion general. Con respecto a la vivienda, el 32% de los pacientes viven en un piso alto sin ascensor, y este porcentaje se mantiene en pacientes a los que se les somete a una amputacion mayor. Conclusiones. Constatamos una tendencia a la exclusion social en los pacientes con isquemia grave de las extremidades. Dicha realidad social debe ser conocida por el cirujano vascular a la hora de tratar a estos pacientes, imponiendose un abordaje multidisciplinar junto con trabajadores sociales, medicos de familia y personal de enfermeria y asistencia domiciliaria. [ANGIOLOGIA 2008; 60: 241–5]

Strong intra- and inter-continental differentiation revealed by Y chromosome SNPs M269, U106 and U152

More than 2700 unrelated individuals from Europe, northern Africa and western Asia were analyzed for the marker M269, which defines the Y chromosome haplogroup R1b1b2. A total of 593 subjects belonging to this haplogroup were identified and further analyzed for two SNPs, U106 and U152, which define haplogroups R1b1b2g and R1b1b2h, respectively. These haplogroups showed quite different frequency distribution patterns within Europe, with frequency peaks in northern Europe (R1b1b2g) and northern Italy/France (R1b1b2h).

A new topology of the human Y chromosome haplogroup E1b1 (E-P2) revealed through the use of newly characterized binary polymorphisms.

Haplogroup E1b1, defined by the marker P2, is the most represented human Y chromosome haplogroup in Africa. A phylogenetic tree showing the internal structure of this haplogroup was published in 2008. A high degree of internal diversity characterizes this haplogroup, as well as the presence of a set of chromosomes undefined on the basis of a derived character. Here we make an effort to update the phylogeny of this highly diverse haplogroup by including seven mutations which have been newly discovered by direct resequencing. We also try to incorporate five previously-described markers which were not, however, reported in the 2008 tree. Additionally, during the process of mapping, we found that two previously reported SNPs required a new position on the tree. There are three key changes compared to the 2008 phylogeny. Firstly, haplogroup E-M2 (former E1b1a) and haplogroup E-M329 (former E1b1c) are now united by the mutations V38 and V100, reducing the number of E1b1 basal branches to two. The new topology of the tree has important implications concerning the origin of haplogroup E1b1. Secondly, within E1b1b1 (E-M35), two haplogroups (E-V68 and E-V257) show similar phylogenetic and geographic structure, pointing to a genetic bridge between southern European and northern African Y chromosomes. Thirdly, most of the E1b1b1* (E-M35*) paragroup chromosomes are now marked by defining mutations, thus increasing the discriminative power of the haplogroup for use in human evolution and forensics.

Footprints of X-to-Y Gene Conversion in Recent Human Evolution

Different X-homologous regions of the male-specific portion of the human Y chromosome (MSY) are characterized by a different content of putative single nucleotide polymorphisms (SNPs), as reported in public databases. The possible role of X-to-Y nonallelic gene conversion in contributing to these differences remains poorly understood. We explored this issue by analyzing sequence variation in three regions of the MSY characterized by a different degree of X-Y similarity and a different density of putative SNPs: the PCDH11Y gene in the X-transposed (X-Y identity 99%, high putative SNP content); the TBL1Y gene in the X-degenerate (X-Y identity 86-88%, low putative SNP content); and VCY genes-containing region in the P8 palindrome (X-Y identity 95%, low putative SNP content). Present findings do not provide any evidence for gene conversion in the PCDH11Y and TBL1Y genes; they also strongly suggest that most putative SNPs of the PCDH11Y gene (and possibly the entire X-transposed region) are most likely X-Y paralogous sequence variants, which have been entered in the databases as SNPs. On the other hand, clear evidence for the VCY genes in the P8 palindrome having acted as an acceptor of X-to-Y gene conversion was obtained. A rate of 1.8 x 10(-7) X-to-Y conversions/bp/year was estimated for these genes. These findings indicate that in the VCY region of the MSY, X-to-Y gene conversion can be highly effective to increase the level of diversity among human Y chromosomes and suggest an additional explanation for the ability of the Y chromosome to retard degradation during evolution. Present data are expected to pave the way for future investigations on the role of nonallelic gene conversion in double-strand break repair and the maintenance of Y chromosome integrity.