Family Studies and Gene Mapping

One of the most successful approach to identify new genes responsible for a disease has been the search of the

full genome in families of affected individuals. A number of genes responsible for several single gene disorders that are inherited in a simple Mendelian fashion, as Huntington's disease and cystic fibrosis, were identified by using this approach. This is not so easy when we come to identify the genetic etiology of complex diseases as osteoporosis, cardiovascular disease, diabetes mellitus etc, where a number of genes each having a small effect together with several environmental factors are responsible for the disease. 



In linkage analysis co segregation of two or more loci (genes or traits) is examined in a family to determine whether the two chromosomes demarked by differing alleles at those loci segregate independently according to Mendel's laws or tend to be inherited together more often than expected, violating Mendel's law. If alleles seem to segregate together more often than expected it is most likely that these alleles lie in very close proximity to each other. Alleles on the same chromosome should segregate together at a rate that is related to the distance between them on the chromosome. 

The measure of genetic linkage is the recombination fraction, which is the probability that a parent will produce a recombinant offspring. Recombination occurs when homologous chromosomes align and cross over during meiosis. In humans the recombination fraction is referred to as θ (theta) and ranges between 0 for completely linked loci and 0.5 for unlinked loci on the same or different chromosomes. The unit of measurement of genetic linkage is usually a centiMorgan (cM). One map unit corresponds to 1cM, which represents 1% recombination or a recombination fraction θ of 0.01, that is equal to 1,000,000 base pairs on the physical map.

The quantitative relationship between frequency of recombination and the distance between genetic loci is not that simple. The existence of crossover at one point may interfere with the formation of other crossovers nearby (positive interference) and also there are regions known as hot spots where a high frequency of recombination occurs. The occurrence of a high frequency of recombination in a limited portion of the genome is known as negative interference. Also recombination rates differ between the sexes with females having a higher rate of recombination.

A genetic map gives the order in which genes occur on a chromosome and the approximate location of a gene of interest. Genetic maps do not require information regarding gene function or any biochemical knowledge and this is very important since most human diseases are observed to have a genetic component but without any further information about them.


Basic steps in gene mapping

Fig.1. Gene Mapping Approach for Common and Genetically Complex disorders (click on the image to enlarge)


As shown in the figure above the classical gene mapping approach (positional cloning) consists of identifying families, sample collection, genotyping, preliminary analyses for initial localization, fine mapping, physical mapping and finally identification of mutations and/or polymorphisms.

A linkage map can be useful to:

Establish the genetic basis of traits

Predict the risk of disease

Localize hereditary disorders to specific regions on the genome (chromosome map or gene map)

Clone genes by positional cloning

Study gene conservation across species and investigate the process of chromosomal evolution




In brief the main steps needed to perform a successful study are:

1. Phenotype definition

The first thing you need to do is to define the phenotype that you are going to map. In this step one must define the clinical parameters and determine and decide what clinical data to collect. It is important to decide what type of analysis to perform, whether it is qualitative or quantitative. In a qualitative type of analysis the assumption is that of whether or not one has the disease or not (osteoporotic or not). On the other hand in a quantitative type of analysis one measures BMD. 

2. Determine that the trait has a genetic component

3. Develop an experimental design

4. Ascertain families

One must decide what type of families to recruit whether to recruit sib-pairs, extended families etc.

5. Collection of biological samples and genotyping

Collection of samples for DNA extraction and genotyping using standard sets of polymorphic markers across the whole genome.

6. Analysis of data

Parametric (LOD score) and/or non-parametric analysis of genotypic data

7. Identification of genomic regions of interest and retesting of these regions

8. Fine mapping of genomic regions to identify the critical region

This can be done in two ways, either to increase the saturation of genotyping of the region and analyse data for linkage and association or by examining the region of interest for genes that might have a biological function related to the trait.

9. Identification of physical maps and gene identification





Haines JL, Pericak-Vance MA 1998 Approaches to gene mapping in complex human diseases. Wiley-Liss, Inc. USA