HUMAN GENETICS

for 1st YEAR STUDENTS


CHROMOSOMAL INHERITANCE

SEX CHROMOSOME ABNORMALITIES

In humans the normal female has two X chromosomes, while the normal male has only one X chromosome. If a gene is on the X chromosome, isn't it logical that there would be twice the gene product in females than there is in males? This was a question that remained unanswered for many years. From biochemical measurements there seemed to be the roughly the same amount of gene product in both males and females. The phenomenon was called "dosage compensation." Somehow the gene knew to compensate for the sex of the individual, either make half as much product if it found itself in a female or make twice as much product if it was in a male. Dosage compensation was explained by the discoveries of Mary Lyon.

LYON HYPOTHESIS

The Lyon hypothesis states that during early development, about the 100 cell stage in humans, one of the X chromosomes in a female gets turned off and this is maintained in all descendant cells of the clone. Which of the two X chromosomes gets turned off in each of the 100 cells is purely a random event except where one of the X chromosomes is abnormal (deletion, insertion, inversion, etc.) An abnormal X is always turned off. However, if there is a translocation between an X chromosome and an autosome, the normal X is turned off and the translocation X remains active. In other words, under normal conditions a female is a mosaic in each tissue derived from somatic cells. If she is a heterozygote for a gene that is on the X chromosome and controls an enzyme, say G6PD, on the average half of her cells will express one allelic product of the G6PD gene and the other half of her cells will express the other allelic product. No somatic cell will express both alleles. This explains the phenomenon of dosage compensation. Only one gene product is produced in each cell of the female and only one gene product is expressed in each cell of the male. However, for some reason both X chromosomes remain active in female germ line cells.

BARR BODIES

The inactive X usually lies along the edge of the interphase nucleus in a highly condensed state. It is always the last to replicate. In 1948, before the discoveries of Lyon, Barr and Bertram found that in the interphase nucleus of female cat neurons there were a significant number of cells that had one "darkly staining body" lying along the edge of the nucleus, but they never found a "darkly staining body" in the neurons of male cats. Similar "darkly staining bodies" are found in buccal epithelial cells of human females, although they can usually be found in only 30% to 40% of the cells. Normal males never express these "Barr bodies." In all cases, the number of Barr bodies is one less than the number of X chromosomes in an individual. One Barr body means the individual has two X chromosomes, two Barr bodies means the individual has three X chromosomes, etc. We now know that the "darkly staining" Barr body is the condensed, inactive X chromosome.

We also know that not all regions of the X chromosome in a female are turned off. There is a blood group locus, Xg, which is near the end of the X chromosome. Heterozygotes for this blood group express both allelic products on each erythrocyte. So there are exceptions to the Lyon hypothesis, but it holds true as a general phenomenon.

Since X inactivation is a random event, sometimes more than half of the cells will have, by chance, the same X inactivated. Rarely, but not as rarely as mutation, so many cells of the heterozygote will share the same inactive X that the female phenotype will appear to be that of the homozygote.

TURNER SYNDROME

Just as simple meiotic nondisjunction is the leading cause of autosomal chromosome abnormalities, so is nondisjunction the leading cause of the X and Y abnormalities. In autosomal abnormalities an increase in nondisjunction was associated with increasing maternal age. In sex chromosome abnormalities, one additional source of nondisjunction can be identified, the problem of X and Y pairing at first meiotic division in spermatogenesis. The X and Y have homology only in a small region (called the pseudo autosomal region) which lies near one end of each chromosome. Rather than pair along their entire length, pairing (and possible recombination) occur only in this small region. At first meiotic division in the male, pairing of X and Y looks more like end to end pairing than longitudinal pairing. This undoubtably adds to the frequency of nondisjunction.

Turner syndrome (45,X) is the most frequent chromosomal abnormality. It is found in more than 7% of all spontaneous abortions. As it affects only about 1/2500 live female births, only about 2% of the recognized 45,X embryos survive to term, 98% are lost. The nondisjunction that results in a 45,X female can occur at either meiotic division in either spermatogenesis or oogenesis, but about 80% are the result of paternal nondisjunction. Turner syndrome individuals can also result from early mitotic nondisjunction, being mosaic 46,XX/45,X.

The phenotype of Turner syndrome individuals differs significantly from the normal female, even though the normal female has only one functioning X chromosome in each cell. The events of embryogenesis during the time both X chromosomes are functioning in the female must be critical, as well as those few regions of the X chromosome that are not inactivated. Refer to Gelehrter, Collins, and Ginsburg, 2nd ed., Chapter 8, for complete descriptions of the phenotypes, and for further details on the sex chromosome abnormalities, including fragile X.

KLINEFELTER SYNDROME

Klinefelter syndrome (47, XXY) occurs in about 1/850 male births. In the human, the presence of one Y chromosome produces male secondary sex characteristics in the absence of specific mutations for sex determining loci. Since the child must get his Y chromosome from his father, the nondisjunction that produces a Klinefelter syndrome child could occur in either meiotic division of the mother, but could only occur in the first meiotic division in the father. If nondisjunction occurred in the father, the zygote would have to get both an X and a Y chromosome in the same sperm. In spermatogenesis this could only result from a mistake in first division. Second meiotic division of spermatogenesis separates either the two X chromatids into different gametes or the two Y chromatids into different gametes.

XYY & XXX SYNDROMES

XYY syndrome occurs in about 1/1000 male births. It can only result from nondisjunction in the second meiotic division of spermatogenesis. Even though it affects only 1/1000 men, it is found in almost 1/50 males in prison populations. Aggressive behavior and less intelligence than siblings are often included in phenotypic descriptions of these 47,XYY individuals.

XXX syndrome (47,XXX) has such a normal phenotype that it is not usually classified as a disease or even recognized unless there are reproductive problems with spontaneous abortions. However, as a general rule, as the number of X chromosomes increases past the diploid state, mental deficiencies increase.

NON-MEIOTIC CHROMOSOMAL ABNORMALITIES

A> number of gross chromosomal changes can arise that results either in altered gene control or in difficulties during meiosis or mitosis. Inversions, non-Robertsonian translocations, and ring chromosomes all produce, or have the potential for producing, altered phenotypes. Each of them is rare when compared to nondisjunction.

INVERSIONS

Inversions involve two chromosomal breaks and rejoining, with the broken piece reincorporated in the opposite orientation from which it naturally occurs. When they include the centromere, they are called pericentric inversions. When they do not include the centromere, they are called paracentric inversions. Both types of inversions arise in mitotic cells. If they arise in precursors of the gametes, they may produce abnormal genomes as they progress through meiosis. Recombination between homologous chromosomes is a necessary part of every normal meiosis. The probability for nondisjunction is greatly increased if there is no recombination. However, recombination between a chromosome with an inversion and its normal homolog may result in two abnormal chromosomes being produced. The results of a paracentric inversion going through meiosis, with a recombination within the inversion, are shown in Figure 10. Of the four gametic products, one is normal, one has the inversion, one has an acentric chromosome, and one has a dicentric chromosome. The acentric chromosome cannot survive. The dicentric chromosome may be pulled apart during mitosis, with a random loss or gain of genetic material.

Paracentric Inversion

Figure 10. Paracentric Inversion.

The results of a pericentric inversion going through meiosis, with a recombination within the inversion is shown in figure 11. Again, four different gametic products are produced, one normal, one has the inversion, and two have duplicated portions and deleted portions. The effect on the phenotype is almost always deleterious, but the magnitude of the effect depends upon the size of the duplications and deletions, and where they occur.

Pericentric Inversion

Figure 11. Pericentric Inversion.

RING CHROMOSOMES

Ring chromosomes result from the loss of the telomeres, with a rejoining of the ends of the same chromosome. When a telomere is lost there is a strong tendency for the chromosome to unite with a similar fragment lacking a telomere. Ring chromosomes cause no problem until there is a sister chromatid exchange. Sister chromatid exchange is a rather common mitotic event. It can be detected in five or six chromosomes at each mitotic division Since the two chromatids are identical in all respects, there is no gain or loss of genetic material. However, when a sister chromatid exchange occurs in a ring chromosome, a double chromatid is produce that is dicentric. Dicentric rings have the same problem going through mitosis as the dicentric chromosomes of paracentric inversions. When the two centromeres line up on opposite sides of the metaphase plate, they migrate to opposite poles, and the chromosome is randomly broken, with loss or gain of genetic material. This always produces a deleterious effect on the phenotype.

NON-ROBERTSONIAN TRANSLOCATIONS

Non-Robertsonian translocations, translocations between chromosomes other than those of the D or G groups, always have trouble going through first meiotic division. One half of the gametes of a person with a translocation will involve duplications of some genetic material and deletions of other portions of the chromosome. These are always deleterious, usually resulting in severely affected individuals.

UNIPARENTAL DISOMY

Included in the discussion of Mendelian traits was a section on imprinting in Prader-Willi syndrome and Angelman syndrome. 75% of the time these diseases are caused by deletion within chromosome 15, more precisely 15q11-13. If the deletion occurs in the chromosome that came from the father (only maternal genes present), Prader-Willi syndrome results. If the deletion occurs in the chromosome that came from the mother(only paternal genes present), Angelman syndrome results. The two syndromes are not at the same genetic locus, but are controlled by genes that are within this small region of chromosome 15. They have very different phenotypes.

Prader-Willi Angelman
Neonatal hypotonia &
developmental deficiency
Ataxia, seizures
Severe obesity Hyperactivity
Short stature Severe mental retardation
Hypogonadism Absence of speech
Mild to moderate mental retardation
with learning disabilities
Inappropriate laughter
(Happy puppet syndrome)
Small hands and feet

In about 25% of Prader-Willi syndrome children, and about 2% of Angelman syndrome children, the cause of the disease is not deletion but uniparental disomy, both copies of chromosome 15 came from one parent. In the case of Prader-Willi syndrome both chromosomes came from the mother. In the case of Angelman syndrome, both chromosomes came from the father. In about 1/30,000 conceptuses the zygote probably was a trisomy 15, a lethal genetic condition, and early in mitotic development one chromosome 15 was lost, restoring the embryo to the diploid state. If the nondisjunction that produced the trisomy 15 occurred in the mother, with the subsequent loss of the paternal chromosome 15, Prader-Willi syndrome results. If the trisomy resulted from paternal nondisjunction with subsequent loss of maternal chromosome 15, Angelman syndrome results. These two mechanisms, deletion and uniparental disomy, account for virtually all of the Prader-Willi syndrome patients. Angelman syndrome can also result from mutations within the gene (or genes) that produce nonfunctional gene products.

Although it is a rare event, uniparental disomy has been documented for other autosomal chromosomes. Except for the unexpected expression of an autosomal recessive disease (heterozygote x homozygous normal mating), no detectable phenotypic effect has been found.


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