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9.3: Chromosome Abnormalities in Humans

The problems described above can affect all eukaryotes, unicellular and multicellular. To better understand the consequences let us consider those that affect people. As you will recall from Figure 2.12, humans are 2n=46. The convention when describing a person's karyotype (chromosome composition) is to list the total number of chromosomes, then the sex chromosomes, and then anything out of the ordinary. Most of us are 46,XX or 46,XY. What follows are some examples of chromosome number and chromosome structure abnormalities.

9.3.1  Down Syndrome

The most common chromosome number abnormality is trisomy-21 or, as it is more commonly known, Down syndrome. Having an extra copy of the smallest human chromosome, chromosome 21, causes substantial health problems.It is present in about 1 in 800 births. Infants with this condition have three copies of chromosome 21 rather than the normal two. Don't confuse trisomy - having three copies of one chromosome (i.e. 2n+1) with triploidy -  having three entire chromosome sets (3x; see Section 2.6.) Females with trisomy-21 are 47,XX,+21 while males are 47,XY,+21. In general, people with Down syndrome are 47,sex,+21 where the word 'sex' signifies that the sex chromosomes may be XX or XY.

Trisomy-21 may arise from a nondisjunction event during meioisis in either parent or during mitosis very early during embryogenesis. However, most cases are due to a first division non-disjunction event occurring in the female parent (Figure 9.14n).

Figure 9.14: This diagram shows the errors during chromosome segregation that cause Down syndrome during meiosis in both parents and fusion of the gametes. Note that the cells that begin meiosis are called meiocytes and that this diagram only shows one of the four cells produced by meiosis. Meiosis occurred properly in the male parent but there was a nondisjunction event in the female parent in anaphase I. (Original-Harrington-CC:AN)

Having an extra copy of the smallest human chromosome, chromosome 21, causes substantial health problems. People with Down syndrome have various degrees of intellectual disability and often have other health problems such as heart defects. The disease was first described by John Down in 1866 but it was not until 1959 when its chromosomal basis was discovered. Current research suggests that at least some of the mental problems are due to having three copies of the DYRK gene on chromosome 21. This gene is active in the brain and there is evidence from humans and from mice that neurons are damaged if there is too much DYRK protein synthesized. 

9.3.2  XYY and XXX

While fetuses trisomic for one of the other larger autosomes seldom survive to term, the situation is quite different for the sex chromosomes. Approximately 1 in 1000 males have an extra Y chromosome and yet most are unaware of it! There is little harm in having two Y chromosomes because they have relatively few genes. Similarly, 1 in 1000 females have an extra X chromosome. This situation is also relatively harmless although for a different reason. Normally in female mammals one of the two X chromosomes is inactivated in each cell so that there can be genetic balance (Figure 9.15n and see Section 3.5.2). In 46,XX females one of the X chromosomes is inactivated while in 47,XXX females two are inactivated.

Figure 9.15: A simplified view of dosage compensation in mammals. Because females have more X chromosomes than males in females one X chromosome is marked as inactive (Xi). It is replicated and transmitted during cell division but most of its genes are silent. It appears as a condensed mass called the Barr body within the interphase nucleus. (Original-Harrington-CC:AN)

9.3.3  Turner Syndrome

Monosomy (2n-1) for autosomal chromosomes does occur at conception, but these embryos almost never survive to term. Similarly, embryos that are 45,Y are also non-viable because they lack many essential genes found on the X chromosome. The only viable monosomy in humans is 45,X, also known as Turner syndrome. These people are phenotypically female because they do not have a Y chromosome (Section 2.5.2). They are viable because in females only one X is active in most cells anyway. People with this condition do have health problems though: they are shorter than average, they have an elevated risk of heart defects, and they are infertile.

The reason for the health problems is that there are a few genes that are found on both the X and the Y chromosome. Because these genes are found in two copies in both XY males and XX females they are in what is called the pseudoautosomal region. This region escapes X chromosome inactivation. One of the genes in this region is called SHOX. It makes a protein that promotes bone growth. 46,XX and 46,XY people have two functioning copies and have average height. People with 47,XYY and 47,XXX genomes have three copies and are taller than average. And people with 45,X have one copy and are short. It is the single copy of SHOX and a few of the other genes in the pseudoautosomal region that causes health problems for women with Turner syndrome.

The reason for the infertility is that the X chromosome inactivation system only acts in somatic cells - it is not needed in the germline cells. Ovaries naturally have two functional X chromosomes. Women with Turner syndrome can not perform oogenesis because this process only works if there are two active X chromosomes. Recently, it has become possible for these women to become pregnant with donated eggs and in vitro fertilization.

9.3.4  Klinefelter Syndrome

There are four common sex-chromosome aneuploidies: 47,XYY, 47,XXX, 45,X, and 47,XXY. This last situation is known as Klinefelter syndrome. These people are male (because they have a Y chromosome) and tall (because they have three SHOX genes). They do not have health problems because the X chromosome inactivation system is independent of sex. In the embryonic nuclei the X chromosome are counted and all but one are shut down. It does not matter whether the embryo is male or female. Men with Klinefelter syndrome have a Barr bodies in their nuclei, the same as 46,XX females. They do have fertility problems because there are two active X chromosome in their testes and this interferes with spermatogenesis. They make enough sperm to conceive children using intracytoplasmic sperm injection though.

9.3.5  Cri-du-Chat Syndrome

Cri-du-chat syndrome occurs when a child inherits a defective chromosome 5 from one parent (Figure 9.16n). This condition is rare - it is present in only 1 in 20,000 to 1 in 50,000 births but it does account for 1% of cases of profound intellectual disability. The specific defect is a deletion that removes 2 Mb or more from the tip of the short arm of the chromosome. In most cases the deletion is the result of a chromosomal rearrangement in one of the parent's germ line cells. People with cri-du-chat have a karyotype of 46,sex,deletion(5).

As with Down syndrome this condition is associated with intellectual disability and other health problems. These problems include an improperly formed larynx which leads to infants making high pitched cat-like crying sounds (hence the name "cry of the cat"). It is suspected that at least some of the intellectual disability phenotype is due to having only a single copy of the CTNND2 gene. This gene is active during embryogenesis and makes a protein essential for neuron migration. Down syndrome and cri-du-chat syndrome are two examples of the need for genomes to contain the proper number of genes. Having too many copies of key genes (Down syndrome) or too few (cri-du-chat syndrome) can lead to substantial developmental problems.

Figure 9.16: A boy with cri-du-chat syndrome. The pictures were taken at 8 months (A), 2 years (B), 4 years (C), and 9 years (D). (Wikipedia-Paola Cerruti Mainardi-CC:AN)

9.3.6  Inversion(9)

The most common chromosome rearrangements in humans are inversions of chromosome 9. About 2% of the world's population is heterozygous or homozygous for inversion(9). This rearrangement does not affect a person's health because the genes on the chromosome are all present - all that has changed is their relative locations. Inversion(9) is different from deletion(5) in two main respects. As mentioned above because it is a balanced rearrangement it does not cause harm. And because of this nearly everyone with an inversion(9) chromosome has inherited it from a parent who had inherited it from one of their parents and so on. In contrast, most cases of deletion(5) are due to new mutations occurring in a parent.