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Box 2.1 Meiosis

Meiosis is a specialized form of cell division occurring in reproductive tissues generating sperm and egg cells. The diploid germ cells undergo DNA replication and two successive rounds of cell division. The genetic complement of the resulting haploid cells comprise one of each pair of homologous chromosomes and is made genetically unique by the independent assortment of chromosomes originally of paternal or maternal origin, and by the reshuffling of genetic material due to homologous recombination, also described as 'crossover events' (Box 2.2). Independent assortment and recombination mean that a person can produce highly variable and distinct individual gametes.

Box 2.2 Homologous recombination (crossing over)

Early in meiosis the cell contains four copies of each chromosome (duplicate pairs of homologous chromosomes) described at this time as chromatids. Homologous recombination results from the process of breakage of non-sister chromatids (one paternal and one maternal chromatid) of a pair of homologues and the rejoining of the fragments to generate new recombinant strands such that there are equal exchanges between allelic sequences at the same positions within the alleles (Fig. 2.1). Homologous recombination is a critical means of generating genetic diversity.

of mendelian characters to map specific disease or trait loci based on segregation within a pedigree of a particular trait and a polymorphic marker (Fig. 2.1). In order to interpret the significance of linkage results, the logarithm of the odds or 'lod score' is used (Chotai 1984; Dawn Teare and Barrett 2005). This describes the recombination fraction (Box 2.3) between a genetic marker and disease locus in terms of a likelihood ratio, in which the null hypothesis is of no linkage between the marker and disease loci (Box 2.4).

In order to analyse cosegregation of genetic loci in family pedigrees, parametric linkage analysis is used. Calculation of a lod score requires a particular genetic model to be specified for the disease under investigation. In fully penetrant mendelian diseases the model would involve the mode of inheritance of the disease and disease allele frequency; models become more complex with incomplete penetrance. Two-point analysis involves estimating linkage between individual genetic markers and a disease locus; multipoint analysis involves at least two markers and is typically used in a small genomic region to localize a disease locus relative to a fixed map of markers.

Non-parametric linkage analysis is used in multifactorial traits without a clear mode of inheritance and does not rely on a particular disease model. In this situation sibling pairs are often analysed looking for excess sharing of alleles that are identical by descent among affected sib pairs more often than would be expected by chance. This approach was used for example to identify linkage to the major histocompatibility complex (MHC) on chromosome 6p21 and other genomic loci for type 1 diabetes (Davies et al. 1994).

2.2.2 Genetic markers

Prior to the availability of genetic markers, a range of other polymorphic characters have been studied including blood group and human leukocyte antigen (HLA) type. Historically association with ABO blood group (OMIM 110300) was defined for a number of diseases including peptic ulcer disease and cancer (Clarke 1959), while for the MHC at chromosome 6p21 the advent of HLA serological testing provided important new evidence of association, notably with autoimmune disease (Chapter 12). However, it was the advent of quantifiable genetic diversity in the form of genetic markers in the 1980s that saw the power of linkage become manifest, in particular when highly polymorphic markers were available in the framework of a genetic map (Botstein et al. 1980; Donis-Keller et al. 1987; NIH/CEPH 1992; Weissenbach et al. 1992; Dib et al. 1996; Broman et al. 1998).

Initial work based on genetic markers used restriction fragment length polymorphisms (RFLPs), typically single nucleotide differences resulting in the gain or loss of a specific sequence recognized by a restriction enzyme (Section 1.2.4) (Botstein et al. 1980). These biallelic markers were increasingly replaced by highly polymorphic minisatellites, then bi-, tri-, or tetranu-cleotide microsatellites which had the advantage of being relatively easy to genotype and highly informative due to the number of different alleles observed in a population for a given marker (Chapter 7) (Weber and

(A) Autosomal dominant pedigree

Recombinant genetic Non-recombinant

Functional variant leading marker genetic marker to disease phenotype

One chromosome inherited from each of parents

Four chromatids generated during

Crossing over (recombination) during meiosis of paternal and maternal chromosomes

Recombination results in two mixed chromatids, two unchanged

Single mixed chromosome transmitted to a particular sperm

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