Haplotype affinities resolve a major component of goat (<i>Capra hircus</i>) MtDNA D-loop diversity and reveal specific features of the Sardinian stock

Goat mtDNA haplogroup A is a poorly resolved lineage absorbing most of the overall diversity and is found in locations as distant as Eastern Asia and Southern Africa. Its phylogenetic dissection would cast light on an important portion of the spread of goat breeding. The aims of this work were 1) to provide an operational definition of meaningful mtDNA units within haplogroup A, 2) to investigate the mechanisms underlying the maintenance of diversity by considering the modes of selection operated by breeders and 3) to identify the peculiarities of Sardinian mtDNA types. We sequenced the mtDNA D-loop in a large sample of animals (1,591) which represents a non-trivial quota of the entire goat population of Sardinia. We found that Sardinia mirrors a large quota of mtDNA diversity of Western Eurasia in the number of variable sites, their mutational pattern and allele frequency. By using Bayesian analysis, a distance-based tree and a network analysis, we recognized demographically coherent groups of sequences identified by particular subsets of the variable positions. The results showed that this assignment system could be reproduced in other studies, capturing the greatest part of haplotype diversity. We identified haplotype groups overrepresented in Sardinian goats as a result of founder effects. We found that breeders maintain diversity of matrilines most likely through equalization of the reproductive potential. Moreover, the relevant amount of inter-farm mtDNA diversity found does not increase proportionally with distance. Our results illustrate the effects of breeding practices on the composition of maternal gene pool and identify mtDNA types that may be considered in projects aimed at retrieving the maternal component of the oldest breeds of Sardinia.</br

Haplotype Affinities Resolve a Major Component of Goat (Capra hircus) MtDNA D-Loop Diversity and Reveal Specific Features of the Sardinian Stock

Goat mtDNA haplogroup A is a poorly resolved lineage absorbing most of the overall diversity and is found in locations as distant as Eastern Asia and Southern Africa. Its phylogenetic dissection would cast light on an important portion of the spread of goat breeding. The aims of this work were 1) to provide an operational definition of meaningful mtDNA units within haplogroup A, 2) to investigate the mechanisms underlying the maintenance of diversity by considering the modes of selection operated by breeders and 3) to identify the peculiarities of Sardinian mtDNA types. We sequenced the mtDNA D-loop in a large sample of animals (1,591) which represents a non-trivial quota of the entire goat population of Sardinia. We found that Sardinia mirrors a large quota of mtDNA diversity of Western Eurasia in the number of variable sites, their mutational pattern and allele frequency. By using Bayesian analysis, a distance-based tree and a network analysis, we recognized demographically coherent groups of sequences identified by particular subsets of the variable positions. The results showed that this assignment system could be reproduced in other studies, capturing the greatest part of haplotype diversity

IRAK-M Is Involved in the Pathogenesis of Early-Onset Persistent Asthma

Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma. IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF-κB and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma

Analysis of MOlecular VAriance after partitioning according to different criteria.

<p>Analysis of MOlecular VAriance after partitioning according to different criteria.</p

Map of Sardinia showing the 34 municipalities (dotted) where sampling was performed.

<p>In the background all municipalities are shaded according to the overall number of goats recorded <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030785#pone.0030785-ISTAT1" target="_blank">[23]</a>, as reported in the left panel (map obtained at <a href="http://www.sar.sardegna.it/servizi/sit/datitematici.asp?wgs=1" target="_blank">http://www.sar.sardegna.it/servizi/sit/datitematici.asp?wgs=1</a>). Sampled municipalities in 5 Sardinian sub regions are shown with the following color codes: Ogliastra-red, Sarrabus-blue, Gerrei-yellow, Iglesiente-purple and Sulcis-green. Detailed names and n. of breeding stations sampled are reported in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030785#pone.0030785.s005" target="_blank">Table S1</a>.</p

Histograms of four summary statistics for DNA diversity from 120 goat breeding stations.

<p>Black arrows point to the value obtained in the overall dataset. In the Tajima's D histogram, significant (nominal p<0.05) values are marked with an asterisk and a normal QQ plot is shown in the inset.</p

Composition of the sample of individuals yielding the set of mtDNA sequences used in all analyses, by provenance and breed.

<p>Composition of the sample of individuals yielding the set of mtDNA sequences used in all analyses, by provenance and breed.</p

Properties of major mtDNA clades.

a<p>. Position in the alignment and allelic state (in bold = derived).</p>b<p>. Entries of a 2×2 contingency table, in the order: With defining sub-haplotype AND In the clade, With defining sub-haplotype AND In other clades or unclassified, With other sub-haplotypes AND In the clade, With other sub-haplotypes AND In other clades or unclassified.</p>c<p>. Not calculated, due to mismatch observed variance lower than mean <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0030785#pone.0030785-Excoffier1" target="_blank">[52]</a>.</p

Median joining network of 419 haplotypes and an outgroup obtained as described in Materials and Methods.

<p>Branch length is not proportional to mutational steps. Node size is proportional to haplotype frequency. The correspondence between node clusters and clades in the NJ tree is reported. Unclassified sequences are blackened.</p