Human genetic diseases and normal variations can be placed into one of five categories:
- single gene disorders (diseases or traits where the phenotypes are largely determined by the action, or lack of action, of mutations at individual loci);
- multifactorial traits (diseases or variations where the phenotypes are strongly influenced by the action of mutant alleles at several loci acting in concert);
- chromosomal abnormalities (diseases where the phenotypes are largely determined by physical changes in chromosomal structure - deletion, inversion, translocation, insertion, rings, etc., in chromosome number - trisomy or monosomy, or in chromosome origin - uniparental disomy);
- mitochondrial inheritance (diseases where the phenotypes are affected by mutations of mitochondrial DNA); and
- diseases of unknown etiology that seem to "run in families."
About 1% of the approximately 4 million annual live births in the United States will have a single gene disorder that will be serious enough to require special medical treatment or hospital care. Each of these single gene disorders, often called Mendelian traits or diseases, is relatively uncommon. The frequency often varies with ethnic background, with each ethnic group having one or more Mendelian traits in high frequency when compared to the other ethnic groups. For example, cystic fibrosis has a frequency of about 1/2000 births in Americans descended from western European Caucasians but is much rarer in Americans of western African descent while sickle cell anemia has a frequency of about 1/600 births in Americans of western African descent but is much rarer in Caucasians. Greeks and Italians of Mediterranean descent have a high frequency of thalassemia; Eastern European Jews have a high frequency of Tay-Sachs disease; French Canadians from Quebec have a high frequency of tyrosinemia, all when compared to other ethnic groups. It has been estimated that each of us, each "normal" member of the human race is carrying between 1 and 8 mutations which, if found in the homozygous state would result in the expression of a Mendelian disease. Since we each have between 50,000 and 100,000 genes (loci) it is unlikely that any two unrelated individuals would be carrying the same mutations, even if they are from the same ethnic background, thus most of our offspring are not suffering from a genetic disease. Most Mendelian diseases are rare, affecting about 1/10,000 to 1/100,000 live births as an order of magnitude estimate. In total they will add to the 1% of live births mentioned above.
Mendelian traits, or single gene disorders, fall into 5 categories or
modes of inheritance based on where the gene for the trait is located
and how many copies of the mutant allele are required to express the
Mendel based his laws on mathematical probabilities that allowed predictions of resulting phenotypes when certain crosses were made in the garden pea. When he published in 1866, the discovery of the chromosomal basis of inheritance (meiosis and gametogenesis) by Sutton, Boveri, and others was still a generation away. Therefore, there was no physical basis for explaining the Mendelian segregation ratios. The discoveries of Sutton, Boveri, and others allowed a reexamination of Mendel's apparently forgotten publication. In 1900, Correns, DeVries, and Tschermak, all independently "rediscovered" Mendel's laws of segregation, and by 1902 the first human Mendelian "inborn error of metabolism", alcaptonuria, was found by Sir Archibald Garrod. Mendel's laws are grounded in the chromosomal movements in meiosis, gametogenesis, and fertilization. Understanding the fundamental processes of cell division is the key to understanding Mendelian genetics.
Mitosis is the process of cell division that is responsible for the development of the individual from the zygote (fertilized egg) to maturity (approximately 1014 cells). It is the process by which the somatic cells divide and maintain the same chromosomal complement. Each chromosome duplicates forming two chromatids connected to a single centromere, the centromeres line up on the metaphase plate without the homologous pairing and recombination found in meiosis (except for sister chromatid exchange of identical DNA information in mitosis), and the centromere divides as each chromatid now becomes a daughter chromosome at anaphase of cell division. Mitosis is the process by which two identical daughter cells with identical DNA complements are formed from one progenitor cell. Mutations can arise during DNA replication in mitosis, just as they do in meiosis. These mutations, and their consequences in somatic cell diseases, such as cancer, are discussed in the molecular genetics lecture portion of this course. Most mitotic divisions, and consequently the fastest rate of growth, occurs before birth in the relatively protected environment of the uterus. Most of us only increase 15 to 30 times our birth weight (24 or 25 times) from birth to maturity, but from conception to birth our weight increases many fold. Consequently, most genetic diseases are expressed at birth or during early development, although some late onset human diseases, and somatic cell diseases, do occur.
Each somatic cell of a normal individual contains two copies of each of the 22 autosomal chromosomes, one of paternal origin and one of maternal origin, and either an X from the mother and an X from the father if the individual is female or an X from the mother and a Y from the father if the individual is male. This is called the diploid (2 copy) state. During gametogenesis, the formation of the gametes (ova in females and sperm in males), this diploid state is reduced to the haploid (1 copy) state through the process of cell division called meiosis. Meiosis consists of two consecutive cytoplasmic divisions with only one DNA replication. In some texts meiosis will be explained as two divisions, a reduction division followed by a mitotic division but this is a misnomer. Meiosis is one continuous process from beginning to end.
This diagram shows a general summary of two pairs of chromosomes going through meiosis. Only the nucleus and the centrioles are shown. In A, the chromosomal DNA is already replicated and the homologous chromosomes are partially paired. In B, pairing is completed but the two chromatids of each chromosome have not yet condensed enough to be visible. In C, both chromotids of each chromosome are visible and recombination (chiasma), or crossing-over, between chromatids of the homologous chromosomes are evident. In D, the chiasmata (pl. of chiasma) are being resolved and the homologous centromeres are lining up on the metaphase plate. E represents anaphase of the first meiotic division. The centromeres of homologous chromosomes are moving to the poles without dividing, thus separating the maternal centromere from the paternal centromere along with their associated chromosomes that have recombined. In F, the centromeres each of the haploid chromosomes with its two chromatids are migrating to the metaphase plate. G shows the centromeres dividing and moving toward the poles in early anaphase of the second meiotic division. H demonstrates the nuclei of the 4 haploid products that result from the meiotic division of one initial diploid cell.
In humans, none of the four haploid products is identical, since recombination occurs at least once for each chromatid, but they all contain the same amount of DNA and each contains 23 chromosomes. The chromosomal movements in oogenesis and spermatogenesis in humans will be covered more completely in the section on chromosomal abnormalities. It is presented here to show the chromosomal movements required to fulfill Mendel's laws.
Mendel assumed that the traits he was studying were determined by what he called unit characters. We call these unit characters alleles. Alleles are the alternative forms of a gene, often called the locus or specific site on the chromosome where the gene resides. Mendel's law of segregation states that during gametogenesis these alternative forms, alleles, segregate into different gametes and are never found in the same gamete. The chromosomal movements in meiosis assure this.
The above sketch reviews the chromosomal movements of first meiotic division. [A], represents two homologous chromosomes in a cell that is going to enter meiosis, one chromosome was inherited from the mother and one inherited from the father. Each chromosome contains a single double stranded DNA molecule. Each has a different allele at a particular locus. [B], the chromosomes have duplicated, forming two chromatids (two double-stranded DNA molecules) and paired at the metaphase plate in the first division of meiosis. [C], the homologous chromosomes have separated at the first division. Notice that the alleles are destined to go into separate gametes. The effects of recombination are not shown.
Mendel's law of independent assortment states that unit characters for different traits, traits controlled by genes of different chromosomes assort independently. That is, if a gene on chromosome 1 has two alleles, a and b, and a gene on chromosome 2 has two alleles, c and d, the combinations a and c, a and d, b and c, and b and d, are all equally likely. There is no preference for a to be with either c or d. Since chromosmes 1 and 2 line up on the metaphase plate independently at the first meiotic division, with equal chance of the maternal or paternal homolog going to one pole for each chromosome, these combinations have an equal chance of occurring. Thus, alleles of genes that lie on different chromosomes assort independently of one another. These two laws, the law of segregation and the law of independent assortment, are the basis of Mendelian inheritance.
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