Insulin-like factor 3 (INSL3) is expressed in Leydig cells of the testis and theca cells of the ovary. This peptide affects testicular descent by acting on gubernaculum via its specific receptor leucine-rich repeat-containing G proteincoupled receptor 8 (LGR8). From initial animal data showing the cryptorchid phenotype of Insl3/ Lgr8 mutants, an extensive search for mutations in INSL3 and LGR8 genes was undertaken in human patients with cryptorchidism, and a frequency of mutation of 4–5% has been detected. However, definitive proofs of a causative role for some of these mutations are still lacking. More recent data suggest additional paracrine (in the testis and ovary) and endocrine actions of INSL3 in adults. INSL3 circulates at high concentrations in serum of adult males and its production is dependent on the differentiation effect of LH. Therefore, INSL3 is increasingly used as a specific marker of Leydig cell differentiation and function.

BACKGROUND:A limited number of studies aimed at investigating the possible association of Y-chromosome haplogroups with microdeletions of the azoospermia factors (AZFs) or with particular infertile phenotypes, but definitive conclusions have not been attained. The main confounding elements in these association studies are the small sample sizes and the lack of homogeneity in the geographical origin of studied populations, affecting, respectively, the statistical power and the haplogroup distribution.MATERIALS AND METHODS:To assess whether some Y-chromosome haplogroups are predisposing to, or protecting against, azoospermia factor c (AZFc; b2/b4) deletions, 31 north Italian patients carrying the AZFc b2/b4 microdeletion were characterised for 8 Y-chromosome haplogroups, and compared with the haplogroup frequency shown by a north Italian population without the microdeletion (n = 93).RESULTS AND DISCUSSION:A significant difference was observed between the two populations, patients with microdeletions showing a higher frequency of the E haplogroup (29.3% vs 9.7%, p<0.01). The geographical homogeneity of the microdeleted samples and of the control population, controlled at microgeographical level, allows the possibility that the geographical structure of the Y genetic variability has affected our results to be excluded.CONCLUSION:Thus, it is concluded that in the north Italian population Y-chromosome background affects the occurrence of AZFc b2/b4 deletions.

Context: An explosive growth in Y chromosome long arm (Yq) microdeletion testing demand for male infertility occurred in the past few years. However, despite the progresses in the biology of this chromosome, a number of molecular and clinical concerns are not supported by definitive data.Objective: The objective was to provide information on the type and prevalence of microdeletions in infertile males, indication for testing, genotype-phenotype correlation, sperm aneuploidies, and genetic counseling.Design and Setting: We performed a prospective study from January 1996 to December 2005 in an academic clinic.Patients: We studied 3073 consecutive infertile men, of which 625 were affected by nonobstructive azoospermia and 1372 were affected by severe oligozoospermia. Ninety-nine patients with microdeletions are described here.Main Outcome Measures: Yq microdeletions, seminal analysis, reproductive hormones, testicular cytology/histology, and sperm sex chromosomes aneuploidies were used as outcome measures.Results: The prevalence of microdeletions was 3.2% in unselected infertile men, 8.3% in men with nonobstructive azoospermia, and 5.5% in men with severe oligozoospermia. Only 2 of 99 deletions were found in men with more than 2 million sperm/ml. No clinical data are useful to identify a priori patients with higher risk of Yq microdeletions. Most deletions are of the AZFc-b2/b4 subtype and are associated with variable spermatogenic phenotype, with sperm present in 72% of the cases. Complete AZFa and AZFb (P5/Proximal P1) deletions are associated with Sertoli cell-only syndrome and alterations in spermatocyte maturation, respectively, whereas partial deletions in these regions are associated with milder phenotype and frequent presence of sperm. Men with AZFc-b2/b4 deletions produce a higher percentage of sperm with nullisomy for the sex chromosomes and XY-disomy.Conclusions: This extensive clinical research expands the knowledge on genotype-phenotype relationships and confirms that the identification of Yq microdeletions has significant diagnostic and prognostic value, adding useful information for genetic counseling in these patients.

Although hominins were present in Europe as early as similar to 780 thousand years ago, there is broad agreement that these archaic humans, including Neanderthals, contributed little to the contemporary European gene pool. In contrast, there is vigorous debate about the relative contributions of humans who entered in the Upper Paleolithic and Neolithic. Here, we argue that the Y-chromosomal diversity pattern is likely to have a largely Neolithic or later origin. In addition to the genome-wide influences resulting from migration, admixture and drift, the effects of positive selection are detectable around some genes, such as lactase. Studies of species associated with humans, e. g. cattle, are providing additional insights.

Three geographic areas of Italy have been sampled and genotyped for 9 Y chromosome STRs: DYS19, DYS385, DYS388, DYS389 I and II, DYS390, DYS391, DYS392, DYS393. Sampling was focused on residents of small areas, well distant from major urban centres. Only individuals whose grandfather would live in the same area were included. A total of 210 unrelated individuals were collected. Distribution of genetic variation across the three samples and comparison with previously published Italian database indicated that so far Y chromosome diversity has been only partially explored in the Italian Peninsula.

The investigation into the genetic diversity of humans has become fundamental to the understanding of the pre-history and history of populations, and it is presently addressing crucial issues concerning human evolution that intersect with demographic, cultural and linguistic events. Numerous studies have been recently focused on the Italian Peninsula, and the current set of data regarding this country can now fit into a general frame in which local differences seems to emerge and be interpreted in the context of other cultural and historical knowledge. However, a comprehensive study based on multiple genetic systems and on extensive sampling is still missing. Here we report new data on the Y chromosome and mitochondrial DNA (mtDNA) over a significantly larger Italian sample. In particular we address four geographic sites that in the past have been the theatre of significant events in the framework of Italy's peopling: Latium (central-west), Piceno (central-east), Calabria (south-west) and Messapia (south-east). Concerning the Y polymorphisms, we based our study on STR and SNP markers in order to tackle population events positioned at various stages of the evolutionary history of Italy on the male side, and to account for local differences. In a similar way, mtDNA has been analyzed for the control region and for a selection of informative mtDNA coding region SNPs. The availability of both sets of loci including slow- and fast-evolving markers has enabled us to undertake multiple-level comparisons. We paid special interest to the distribution of genetic variability across our populations and we aimed to compare the mainframe emerging from the haploid male and female inherited loci. Preliminary results provided us with intriguing inferences regarding the prehistory and history of Italy.

In women, single nucleotide polymorphisms (SNP) of the FSH receptor (FSHR) gene influence FSH concentrations and the sensitivity of the FSHR to FSH in vivo. In contrast, the significance of FSHR R gene SNP in the male is poorly understood. To this aim, the possible role of three FSHR SNP was evaluated in male infertility. SNP in exon 10 (codon 307 and 680) and in the core promoter region (at position -29) of the FSHR gene were analysed by polymerase chain reaction-restriction fragment length polymorphism technique in 150 men representative of the general population, 107 proven fathers, 92 normozoospermic controls, and 215 infertile patients classified according to sperm parameters (38 azoospermia, 53 severe oligozoospermia, 48 moderate oligozoospermia, and 76 slight oligozoospermia). Reproductive hormones were measured in infertile males and normozoospermic controls. No significant difference was found in allelic variants frequency and genotype distribution between each category of subjects when analysing the FSHR exon 10 SNP alone and in combination with the SNP at position -29. Serum FSH concentrations and other andrological parameters did not differ between subjects with different genotype within each group. The data showed that in the Italian population, FSHR genotypes have no influence on FSH concentrations both in normal and infertile males and do not associate with spermatogenetic impairment.

Genetic causes account for 10–15% of severe male infertility, including chromosomal aberrations and single gene mutations. Natural selection prevents the transmission of mutations causing infertility, while this protective mechanism may be overcome by assisted reproduction techniques. Consequently the identification of genetic factors has become good practice for appropriate management of the infertile couple. Furthermore, patients affected by some forms of genetic alterations produce a higher frequency of sperm with aneuploidies. Sperm aneuploidies are the direct result of the constitutional genetic abnormality or are caused by meiotic errors induced by the altered testicular environment that these men present. In this review we will report and discuss the genetic causes of male infertility known up to date and we will analyse genetic polymorphisms possibly associated with male infertility.

The Italian peninsula, given its geographical location in the middle of the Mediterranean basin, was involved in the process of the peopling of Europe since the very beginning, with first settlements dating to the Upper Paleolithic. Later on, the Neolithic revolution left clear evidence in the archeological record, with findings going back to 7000 B.C. We have investigated the demographic consequences of the agriculture revolution in this area by genotyping Y chromosome markers for almost 700 individuals from 12 different regions. Data analysis showed a non-random distribution of the observed genetic variation, with more than 70% of the Y chromosome diversity distributed along a North–South axis. While the Greek colonisation during classical time appears to have left no significant contribution, the results support a male demic diffusion model, even if population replacement was not complete and the degree of Neolithic admixture with Mesolithic inhabitants was different in different areas of Italy.

We have typed 275 men from five populations in Algeria, Tunisia, and Egypt with a set of 119 binary markers and 15 microsatellites from the Y chromosome, and we have analyzed the results together with published data from Moroccan populations. North African Y-chromosomal diversity is geographically structured and fits the pattern expected under an isolation-by-distance model. Autocorrelation analyses reveal an east-west cline of genetic variation that extends into the Middle East and is compatible with a hypothesis of demic expansion. This expansion must have involved relatively small numbers of Y chromosomes to account for the reduction in gene diversity towards the West that accompanied the frequency increase of Y haplogroup E3b2, but gene flow must have been maintained to explain the observed pattern of isolation-by-distance. Since the estimates of the times to the most recent common ancestor (TMRCAs) of the most common haplogroups are quite recent, we suggest that the North African pattern of Y-chromosomal variation is largely of Neolithic origin. Thus, we propose that the Neolithic transition in this part of the world was accompanied by demic diffusion of Afro-Asiatic-speaking pastoralists from the Middle East.

This study analyzes the variation of six binary polymorphisms and six microsatellites in the Mbenzele Pygmies from the Central African Republic. Five different haplogroups (B2b, E(xE3a), E3a, P and BR(xB2b,DE,P)) were observed, with frequencies ranging from 0.022 (haplogroup P) to 0.609 (haplogroup E3a). A comparison of haplogroup frequencies indicates a close genetic affinity between the Mbenzele and the Biaka Pygmies, a finding consistent with the common origin and the geographical proximity of the two populations. The haplogroups P, BR(xB2b,DE,P) and E(xE3a), which are rare in sub-Saharan Africa but common in western Eurasia, were observed with frequencies ranging from 0.022 (haplogroup P) to 0.087 (haplogroup E(xE3a)). Thirty different microsatellite haplotypes were detected, with frequencies ranging from 0.022 to 0.152. The Mbenzele share the highest percent of microsatellite haplotypes with the Biaka Pygmies. Five out seven haplotypes which are shared by the Mbenzele and Biaka Pygmies belong to haplogroup E3a, which suggests that they are of Bantu origin. The plot based on F(st) genetic distances calculated using microsatellite data provides a picture of population relationships which is in part congruent and in part complementary to that obtained using haplogroup frequencies. Finally, the Mbenzele and Biaka Pygmies were found to be markedly more genetically similar using Y-chromosomal than autosomal microsatellites. We suggest that this could be due to the higher phylogenetic stability of Y-chromosome and to the effect of the male-biased gene flow during the Bantu expansion.

We investigated Y chromosome populations structure in the Italian peninsula by means of a number of microsatellites and SNPs markers. Genetic analysis revealed a certain degree of heterogeneity between samples at both haplotype (hpt) and haplogroup (hg) level. Implications in genetic history and forensic are discussed.

We have established the use of a primer extension/mass spectrometry method (the PinPoint assay) for high-throughput SNP genotyping of the human Y chromosome. 118 markers were used to define 116 haplogroups and typing was organised in a hierarchical fashion. Twenty multiplex PCR/primer extension reactions were set up and each sample could be assigned to a haplogroup with only two to five of these multiplex analyses. A single aliquot of one enzyme was found to be sufficient for both PCR and primer extension. We observed 100% accuracy in blind validation tests. The technique thus provides a reliable, cost-effective and automated method for Y genotyping, and the advantages of using a hierarchical strategy can be applied to any DNA segment lacking recombination.

To define Y-chromosome haplotypes, we studied seven biallelic polymorphic sites. We combined data with those from four dinucleotide-repeat polymorphisms, to establish Y-chromosome compound superhaplotypes. Eight biallelic haplotypes that matched the dendrogram proposed by other investigators were identified in 762 Y chromosomes from 25 African populations. For each biallelic site, coalescence time of lineages carrying the derived allele was estimated and compared with previous estimates. The "ancestral" haplotype (haplotype 1A) was observed among Ethiopians, "Khoisan" (!Kung and Khwe), and populations from northern Cameroon. Microsatellite distributions within this haplotype showed that the Khoisan haplotypes 1A are widely divergent from those of the other two groups. Populations from northern Africa and northern Cameroon share a haplotype (i.e., 1C), which is not observed in other African populations but represents a major Eurasian cluster. Haplotypes 1C of northern Cameroon are clearly distinct from those of Europe, whereas haplotypes 1C of northern African are well intermingled with those of the other two groups. Apportionment of diversity for the Y-chromosomal biallelic haplotypes was calculated after populations were clustered into different configurations. Despite some correspondence between language affiliation and genetic similarity, geographic proximity seems to be a better predictor of genetic affinity.