Compared with other mammals, humans as a species are relatively infertile. Various studies suggest that in young, unselected couples, who are trying to conceive, 20–25% of them should be successful each monthly cycle (Bonde et al. 1998; Edwards & Brody, 1995). This compares with an average of 70% in captive baboons for example (Stevens, 1997). Interestingly, the implantation rate after in vitro fertilisation (IVF) at best averages around 20% per embryo transferred (Edwards & Beard, 1999). Evidence is steadily accumulating to prove that the major cause of implantation failure in humans after both in vivo and in vitro fertilisation is the high incidence of chromosomal abnormality. Combining data from cytogenetic studies of spontaneous abortions with those obtained from preimplantation embryos suggests that meiotically derived aneuploidy occurs in 25% of conceptions, an order of magnitude higher than is found in other well studied species such as the mouse (Hassold & Jacobs, 1984; Jamieson, 1994). Additionally, interphase fluorescent in situ hybridisation (FISH) analysis of three day old human embryos has shown that up to 50% are chromosomally mosaic (Delhanty et al. 1997; Munné et al. 1998), further increasing the chance of implantation failure. This review covers the evidence accumulating from a variety of sources that poor fertility in humans has a chromosomal basis.

In this work we focus on a microsatellite-defined Y-chromosomal lineage (network 1.2) identified by us and reported in previous studies, whose geographic distribution and antiquity appear to be compatible with the Neolithic spread of farmers. Here, we set network 1.2 in the Y-chromosomal phylogenetic tree, date it with respect to other lineages associated with the same movements by other authors, examine its diversity by means of tri- and tetranucleotide loci and discuss the implications in reconstructing the spread of this group of chromosomes in the Mediterranean area. Our results define a tripartite phylogeny within HG 9 (Rosser et al. 2000), with the deepest branching defined by alleles T (Haplogroup Eu10) or G (Haplogroup Eu9) at M172 (Semino et al. 2000), and a subsequent branching within Eu9 defined by network 1.2. Population distributions of HG 9 and network 1.2 show that their occurrence in the surveyed area is not due to the spread of people from a single parental population but, rather, to a process punctuated by at least two phases. Our data identify the wide area of the Balkans, Aegean and Anatolia as the possible homeland harbouring the largest variation within network 1.2. The use of recently proposed tests based on the stepwise mutation model suggests that its spread was associated to a population expansion, with a high rate of male gene flow in the Turkish–Greek area.

During recent years the HRAS1 minisatellite has been analysed by several authors because of its putative association with cancer susceptibility. The aim of this report is to test the usefulness of this minisatellite in investigating human population relationships. We have studied 370 chromosomes from two well-differentiated populations: Galicia (North-west Iberia) and South-east Africa, as well as available data on allele length gene frequencies. The fragment analysis results show a strong tendency to differentiate between non-African and African populations. In spite of the usefulness of fragment analysis, the minisatellite variant repeat (MVR) approach of the HRAS1 minisatellite appears to be a more powerful method for use in human population studies, due to the high level of diversity of its interspersion pattern structures. In addition, this approach has allowed us to define some new structural characteristics of this minisatellite. Four different major groups of human HRAS1 minisatellite alleles could be distinguished following a structural criterion based on the MVR code. Furthermore, the characterisation of the HRAS1 minisatellite in chimpanzees revealed clear differences when compared to humans, not only with respect to the allele size but also to the internal structure.

DNA was extracted from specimens derived from the calcaneus of the Tyrolean Ice Man under sterile conditions in a laboratory, where no DNA extractions and PCR experiments had been performed before. Agarose gel electrophoresis and ethidium bromide staining did not reveal any evidence of genomic DNA in the preparation obtained, indicating a high degree of DNA degradation. Nevertheless, we performed PCR amplifications with this sample using primer pairs specific for HLA class II alleles. HLA-DRB and DQB1 alleles were amplified in a nested PCR approach. In one of the reactions, we observed a distinct amplification product, which we directly sequenced. By comparing the obtained nucleotide sequence with a database of HLA alleles we assigned the HLA-DRB1*1402 type to the amplified sample. None of the investigators involved possesses this allele, indicating that no contamination with modern DNA had occured. The HLA-DRB1*1402 allele is extremely rare in Europe, but is common in Inuits and South American Indians and has previously only once been identified in the laboratory.

In Danes we replicated the 3′APOB–VNTR gene/longevity association study previously carried out in Italians, by which the Small alleles (less than 35 repeats) had been identified as frailty alleles for longevity. In Danes, neither genotype nor allele frequencies differed between centenarians and 20–64-year-old subjects. However, when Danish and Italian data were compared, a significant difference (p = 0.0004) was found between the frequencies of Small alleles in youths, which disappeared in centenarians (p = 0.290). Furthermore, the demographic-genetic approach revealed in Danes a significant gene–sex interaction relevant to Long alleles (more than 37 repeats). The different findings in Denmark and Italy suggest that gene/longevity associations are population-specific, and heavily affected by the population-specific genetic and environmental history.

Susceptibility to coeliac disease has a strong genetic component. The HLA associations have been well described but it is clear that other genes outside this region must also be involved in disease development. Two previous genome-wide linkage studies using the affected sib pair method produced conflicting results. Our own family based linkage study of 16 highly informative pedigrees identified 17 possibly linked regions, each of which produced a result significant at p < 0.05 or less.

We have now investigated these 17 regions in a larger set of pedigrees using more finely spaced markers. Fifty multiply affected families were studied, comprising the 16 pedigrees from the original genome screen plus 34 new highly informative pedigrees. A total of 128 microsatellite markers were genotyped with an average spacing between markers of 5 cM. Two-point and three-point linkage analysis using classical and model free methods identified five potential susceptibility loci with heterogeneity lod scores > 2.0, at 6p12, 11p11, 17q12, 18q23 and 22q13.3. The most significant was a heterogeneity lod of 2.6 at D11S914 on chromosome 11p11. This marker maps to a position implicated in one of the two previous genome scans and taken together these results provide strong support for the existence of a susceptibility locus in this region.

We demonstrate the use of Grade-of-membership (GoM) (Manton et al. 1994) for sibpair linkage analysis: GoM was used to map the IDDM11 locus to the region of chromosome 14q24.3 identified by Field et al. (1996). Haplotype groups were constructed from sib pair information on the number of shared alleles. The sample consisted of 578 sibling pairs found in 246 multiplex IDDM families. Both siblings were diabetic in 53% of the pairs (AA). Pair members could share 0, 1 or 2 alleles IBS at each of eight linked marker loci spanning IDDM11. Three model-based groups best represented the data on allele sharing: the groups corresponded to ‘No’, ‘One’ and ‘Two’ shared haplotypes for the region. Group ‘Two’ was larger (37% vs. 25%, p<0.0001) and more homogeneous (p<0.0001) than expected by chance consistent with the IDDM11 locus being a determinant of diabetes in multiplex families. Genetic linkage of IDDM to the region was demonstrated by a 19% increase in the proportion of AA pairs over the haplotype groups: ‘No’, 42%; ‘One’, 49%; ‘Two’, 61%, p = 0.0005, representing a 43% relative increase.

The development of the theory of estimation of gametic disequilibrium for multiallelic systems is particularly necessary, since a large number of the genetic markers available at present are highly polymorphic multiallelic systems. The D′ coefficient is one of the most commonly used measures of the extent of overall disequilibrium between all possible pairs of alleles at two multiallelic loci. Nevertheless, the sampling properties of this measure of overall disequilibrium, are to date, unknown. In this work, we have derived explicit expressions by large-sample theory to compute the approximate sampling variance of Dˆ′ between pairs of multiallelic loci, when samples of haplotypes are taken from populations. Formulae for calculating the asymptotic sampling variance were checked by Monte Carlo simulation. In addition, the magnitude of the sampling variance of Dˆ′ was investigated under different scenarios of disequilibrium between multiallelic loci. Extensive simulations were also carried out for describing the sampling distribution of Dˆ′, conditioned on the sample size, number of alleles and their frequencies, and disequilibrium components. It was found that the sampling distribution of Dˆ′ generally approaches well the theoretical normal distribution for experimental sample sizes, particularly when loci have many alleles. Disequilibrium data between microsatellite loci of human chromosome 11p are used for illustration. These investigations increase substantially our knowledge about this widely used measure of overall disequilibrium, which is relevant to evaluate disequilibrium between multiallelic loci in populations.