Genomics- The Science and Technology Behind the Human Genome Project. Charles R. Cantor, Cassandra L / genomics1-10 / 6

Figure 6.3 Examples of cases where particular combinations of alleles in parents and offspring confound attempts to trace genetic events uniquely.

BOX 6.1

MEIOSIS

The process of meiosis and the recombination events that occur during meiosis, are actually much more complicated than the simple picture given in the text. Figure 6.4 illustrates this process for the relatively simple case of a cell with only two different chromosomes. The parental cell is diploid; it contains two copies of each homologous chromosome. When this cell duplicates its genome, in preparation for cell division, it

and associate, as shown in Figure 6.4. The resulting structures are pairs of homologous chromosomes, each containing two paired sister chromatids (identical copies of each other). Thus, altogether, four DNA molecules (eight DNA strands!) are involved in close proximity. In order for these molecules to separate, there appears to be an obligatory recombination event that involves at least one chromatid from each pair of the homologous chromosomes. As shown in Figure 6.4, this results in a reciprocal exchange

of DNA between two chromatids, while, in the simple case illustrated, the other two chromatids remain unaltered.

The homologous chromosomes segregate to separate daughter cells during the last stages of the first meiotic division. When this is completed, the result is two diploid cells as in ordinary mitotic division. However, what is profoundly different about these cells is that each contains paired homologous chromosomes that now consist of some regions where both copies of the homolog arose by duplication of a single one of the initial homologous pairs. Because of recombination, one member of each chromosome

pair at this point contains some material that is a mosaic of the two original parental homologs. In the second meiotic cell division, each the pair of homologous chromosomes is segregated into a separate daughter cell that goes on, eventually, to become a

170 GENETIC ANALYSIS

A GLOSSARY OF GENETIC TERMS

The science of genetics emerged and matured before DNA was known to be the genetic material. Many terms and concepts were coined without a knowledge of their chemical basis. Here we define some of the commonly used genetic terms needed to follow arguments in human genetics, and we provide an indication of their molecular basis. The first few of these notions are illustrated schematically in Figure 6.5.

Gene. A commonly used term for a unit of genetic information sufficient to determine an observable trait. In more contemporary terms, most genes determine the sequence and structure of a particular protein molecule. However, genes may code for untranslated RNAs like tRNA or rRNA, or they may code for more than one different protein when complex mRNA processing occurs.

Locus. A site on a chromosome, that is, site on a DNA molecule.

Allele. A variant at a particular locus, namely a DNA sequence variant (simple or complex) at the particular locus of interest.

Homozygosity. The two homologous chromosomes in a diploid cell have the same allele at the locus of interest.

cell or offspring. Thus, considering only two chromosomes in Figure 6.6, there will be four possible types of gametes (neglecting recombination), and each of these will occur at equal frequencies.

Figure 6.6 Independent segregation of alleles on two different chromosomes. Shown are parental genomes and possible gametes arising from these genomes.

Phenotype. What one sees, namely the complete set of observable inherited characteristics of an organism, or the particular set of characteristics controlled by the locus or loci of interest.

Genotype. What one gets, namely the genetic constitution, which is the particular set of alleles inherited by the organism as a whole, or for the particular locus or loci of interest.

Haplotype. The actual pattern of alleles on one chromosome, that is, on a single DNA molecule.

Dominant. An allele that produces an identical phenotype if it is present on one homologous chromosome, or on both. True simple dominant traits are rare in the human; one example may be Huntington’s disease where individuals carrying one or two disease alleles appear to have indistinguishable disease phenotypes.

use precise enough definitions and measurements.

Penetrance. The chance that an allele yields the expected phenotype. This term covers a multitude of sins and oversimplifications. In simple genetic systems the penetrance should normally be 1.0. In outbred species like the human, there can be unknown ge-

netic variants that interact with the gene product at the locus in question and produce different phenotypes in different individuals. Purely at the DNA level we expect all phenotypes to be distinguishable and to show complete penetrance because the pheno-

type at the level of DNA is identical to the genotype. An exception occurs if the phenotype requires the expression of a particular allele in an environmental context that

map. Both must ultimately reflect the DNA sequence of the chromosome. However, the genetic map is based on recombination frequencies, while the physical map is based directly on measurements of DNA structure. The meiotic recombination frequency is not uniform along most chromosomes. Regions are observed where recombination is much more frequent than average, hot spots, and where recombination is much less frequent than average, cold spots.

spots. Attempts to narrow them down to short specific DNA sequence elements have not yet succeeded in mammalian samples. However, we do know that recombination hot spots can,

themselves, be inherited alleles. This can lead to serious complications in trying to interpret genetic maps directly in terms of relative physical distances along the DNA.

Two other complications can lead to errors in the construction of genetic maps, and confuse the issue when these maps are compared directly with physical maps. If not properly identified and accounted for, both can lead to inconsistent evidence for gene order. Multiple crossovers can occur between a pair of DNAs strand during meiotic recombination. One schematic example of this is given in Figure 6.9, and the consequences for puta-

Figure 6.9 A more detailed view of meiotic recombination showing the association between pairs of homologous chromosomes after DNA synthesis, and the possibility of multiple crossovers before segregation.