Linkage

In linkage studies, rather than just studying the segregation of a disease in families, the co-segregation of the disease and a set of genetic markers is investigated. The aims are, first, to detect linkage, indicated by the disorder and the marker co-occurring more often than would be expected by chance (i.e. not showing Mendelian independent assortment) and, second, to estimate the distance between a linked marker and the gene conferring to susceptibility to the disorder.

It is possible to detect linkage only in families containing at least one parent who is a double heterozygote (i.e. heterozygous at both the marker and the disease loci). Technically such families are referred to as double back-cross or intercross/intercross matings but, for simplicity, we will just focus on the double back-cross type (Table .2). The table shows a double hetrozygote parent where the alleles A and B are on one chromosome with a and b on the other. Consequently offspring of the types aaBb or Aabb result from recombination or crossing over between the homologous pair of chromosomes during meiosis. These types of offspring are called recombinants. Offspring of the same type as the parents (i.e. AaBb aabb are non-recombinant. We can then simply define the recombination fraction, q, as the number of recombinants divided by total number of offspring.

firtrrtl

i

PkMl

«M m

Ghftit V®

jflto

dtU,

Noo-

rKWTÉflim (Usnntiram ÎKontfart nnontfirf

H**® X 3t

X

Ï

Lii^i IHfi NÎ

«

MA

Table 2 Double back-cross mating

Table 2 Double back-cross mating

For two loci that are very widely separated on the same chromosome (and all pairs of loci carried on to two different chromosomes) independent assortment occurs and q = 1/2. When the two loci are close together dependent assortment may be observed indicated by a recombination fraction of less than a half. The size of the recombination fraction depends on the physical distance between the two loci and (within certain limits) is proportional to it, so that for loci that are very close together recombination rarely occurs and q tends to zero. Genetic distances estimated by linkage studies are measured in centimorgans (cM) with 1 cM the equivalent of a recombination fraction of 0.01. For reasons that are not fully understood, recombination occurs more frequently in female than in male meioses. Hence, the size of the female human genome expressed in centimorgans is larger than the male genome. The sex-averaged size of the human genome is about 3700 cM. With reasonable sample sizes major gene effects can be confidently detected over distances of around 10 to 15 cM. Hence, a whole genome search can be carried out using 200 to 300 polymorphic markers, provided they are approximately evenly spaced. A polymorphism can be defined as a gene or sequence of DNA that occurs in two or more common forms. Classically, 'common' means an allele frequence of at least 1 per cent. However, modern markers such as simple sequence repeat polymorphisms are generally highly polymorphic having multiple very common alleles. Since, as we have noted, heterozygosity in the parental generation is a prerequisite for linkage analysis, simple sequence repeat polymorphisms are much more often informative than earlier less polymorphic types of marker.

Beat Depression Today

Beat Depression Today

I know this is hard for you to believe. I mean, to be able to be totally free of depression in such little time... and without any effort... not to mention the freedom to live your life, appear hard to fulfill at first glance... That is until you know the facts On a subconscious level, you will experience an incredible and exclusive Tri- Enhanced trance state of hypnosis to reprogram your mind to free you from negatize emotions.

Get My Free Ebook


Post a comment