Biology Reference
In-Depth Information
types of DNA sequence variants that can be used in linkage analysis. The
oldest, restriction fragment length polymorphisms (RFLPs), owing to their
limited variation, have almost exclusively been replaced by a subset of vari-
able number tandem repeats (VNTRs) known as microsatellites. The latter
are likely to be succeeded in the near future by single nucleotide polymor-
phisms (SNPs).
VNTR polymorphisms are due to the presence of a different number of
tandem repeats of short DNA sequences including either di-, tri- or tetranu-
cleotide repeats known as short tandem repeats (STRs). The most com-
monly used VNTRs are dinucleotide repeats which occur some 50,000 to
100,000 times in the genome and consist of blocks of variable numbers of
tandem repeats of the dinucleotide CA : GT constituting so-called CA
repeats or microsatellites (Weber and May 1989). Microsatellites are highly
polymorphic and some 8,000 or more have been identified (Weissenbach
et al. 1992; Gyapay et al. 1994; Dib et al. 1996) and mapped to the human
genome providing a skeleton framework of the human genome for linkage
analysis.
More recently, a third generation of polymorphic DNA variants based on
single nucleotide polymorphisms (SNPs) have been identified (Wang et al.
1998b). Some 700 to 900 SNPs at appropriate intervals throughout the
genome will allow the possibility of mapping a disorder in a single analysis
by DNA chip technology (Kruglyak 1997).
2.3 Recombination Fraction
The recombination fraction is the probability that a crossing-over event will
occur between two loci in meiosis. It is designated by the symbol
q. If two
loci are not linked, i.e. are on different chromosomes or are very far apart
on the same chromosome, then the chance that they segregate indepen-
dently is 50% and therefore q=0.5. If, however, in 19 out of 20 meioses the
alleles at two loci segregate together, then they are on the same chromo-
some and they are said to be linked with q=0.05.
The unit of measurement of linkage map distance between two loci is the
morgan. One Morgan, or 100 centiMorgans (cM), is defined as the map dis-
tance in which an average of one crossover per chromosome strand occurs.
Over very small distances, the probability of more than one crossover is
negligible. Thus, for example, if two loci are one cM apart, then a crossover
would be expected to occur between them once in every 100 meioses, and
q=0.01. The human genome is estimated by recombination studies to be
3,000 cM in length. The physical length of the human genome is approxi-
mately 3 ¥ 10
9
base pairs (bp), so on average, one cM corresponds to
10
6
bp. The relationship between genetic distance and physical length is not,
however, linear because crossing-over is a nonrandom process with some
regions being recombination “hotspots” and vice versa; also, recombination
occurs more frequently in female than in male meioses.
