Human chromosomes are complex structures consisting of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and protein. Each single helix of DNA is bound at each end with a telomere and has a centromere somewhere along the length of the chromosome. The telomere protects the ends of the chromosome during DNA replication. Telomere shortening is associated with aging. The centromere is the site at which the mitotic spindle will attach and is necessary for proper segregation of chromosomes during cell division. The centromere divides the chromosome into two arms, identified as p (petit) for the short arm and q for the long arm. The centromere can be positioned anywhere along the arm of the chromosome and its location has been used to group like chromosomes together as central (metacentric), distal (acrocentric) or others (submetacentric). The length of the chromosome plus the position of its centromere are used to identify individual chromosomes within the 22 pairs of autosomes and one pair of sex chromosomes. Chromosomes are numbered in descending order of size; 1 is the largest. The only exception to this rule is chromosomes 21 and 22; 22 is larger than 21. Because of the historical convention of associating Down syndrome with trisomy 21, this chromosome pair was not renamed when the size difference became apparent.
A karyotype is a display of chromosomes ordered from 1 to 22 plus the sex chromosomes, with each chromosome oriented so that the p arm is on top. Females have a 46XX karyotype and males a 46XY karyotype (Fig. 4.1a and b).
Mitosis and meiosis
These are two distinct types of cell divisions, with several common features. The first is the need to duplicate the entire chromosome content of the cell prior to division. Both also use the cell machinery of the parent cell to make the DNA, RNA and new proteins that will participate in the cell division. Finally, both processes rely on using the mitotic spindle to separate the chromosomes into the two poles of the cell that are destined to become the progeny of that cell. Mitosis and meiosis differ in that duplicated chromosomes behave differently after DNA replication (Fig. 4.2). In mitosis, there is no difference in total chromosome content between parent and daughter cells; in meiosis, the chromosome number of the daughter cells is eventually reduced from 46 to 23, which is necessary to convert the diploid germ cell precursors originating in the embryo into haploid (1n) germ cells. These haploid germ cells will produce a new diploid organism at fertilization. Meiosis promotes exchange of genetic material through chromatid crossing over; mitosis does not.
During the interphase preceding cell division, the DNA for each chromosome is duplicated to 4n. Thus, each chromosome consists of two identical chromatids joined at the centromere.
In mitosis, the chromosomes first shorten and thicken and the nucleoli and nuclear membrane break down (prophase). During metaphase, a mitotic spindle forms between the two centrioles of the cell and all chromosomes line up on its equator. The centromere of each chromosome splits and one chromatid from each chromosome migrates to the polar ends of the mitotic spindle (anaphase). In telophase, new nucleoli and nuclear membranes form, the parent cell divides into two daughter cells and the mitotic spindle is disassembled. Two genetically identical cells now exist in place of the parent cell. Mitosis is a non-sexual or vegetative form of reproduction.
Meiosis involves two sequential cell divisions, again beginning with the 4n DNA produced in interphase. In prophase of the first division (prophase 1), several specific and recognizable events occur. In the leptotene stage, the chromosomes become barely visible as long thin structures. Homologous pairs of chromosomes then come to lie side by side along parts of their length, forming tetrads (zygotene stage). The chromosomes thicken and shorten, much as they do in mitotic prophase (pachytene stage); however, the pairing that occurred in the zygotene stage allows synapsis, crossing-over and chromatid exchange to happen. In the diplotene/diakinesis stage, the chromosomes shorten even more. The paired homologous chromosomes show evidence of the crossing-over and chromatid exchange, displaying characteristic chiasmata that join the chromosome arms. Loops and unusual shapes within the chromosomes may be apparent at this stage. In metaphase 1 of meiosis, the nuclear membrane breaks down and the joined pairs of homologous chromosomes line up at the equator of the spindle apparatus. One of each pair of homologous chromosomes then moves to each end of the cell along the spindle (anaphase 1). Nuclear membranes may then form, yielding two haploid daughter cells with 23 2n chromosomes in telophase 1. In the second meiotic division, these haploid cells divide as if in mitosis. This second division produces four haploid cells each containing 23 1n chromosomes. Unlike the cells produced in mitosis, these daughter germ cells are genetically unique and different from the parent cells because of the genetic exchanges that took place in the diplotene stage. Haploid germ cells participate in sexual reproduction in which a sperm cell and oocyte come together to form a new diploid zygote.
While the sequence of events in meiosis during spermatogenesis and oogenesis is basically the same, there are several important differences. In the prepubertal male, primordial germ cells are arrested in interphase. At puberty, these cells are reactivated to enter rounds of mitoses in the basal compartment of the seminiferous tubule. These reactivated cells are known as spermatogonial stem cells. From this reservoir of stem cells, early spermatogonia emerge and divide several times again to produce a “clone” of sperma togonia with identical genotypes. All the sperma togonia from the clone then entermeiosis 1 and 2 toproduce unique haploid sperm. New stem cells are constantly entering the spermatogenic cycle (Chapter 8) and thus the sperm supply is constantly renewing itself. Because of the relatively short time for spermatocytes to progress through meiosis and because of the tremendous competition among spermatozoa to reach the single oocyte within the female tract, fertilization of an egg by an aneuploid sperm is far rarer than the converse.
In contrast to the testis, the ovary of a female at birth contains all the germ cells it will ever have. These oocytes remain arrested in prophase 1 of meiosis until the LH surge at ovulation initiates met- aphase 1. Thus, the duplicated genetic material within the oocyte exists paired with its homologous chromosome for 10–50 years before the cell is called upon to divide. For this reason alone, oocytes are much more prone to chromosome abnormalities than are sperm.
This is the failure of a chromosome pair to separate during meiosis, and can occur at either meiosis 1 or 2. When a single chromosome is involved, the aneuploid zygote is either monosomic or trisomic for the chromosome pair that failed to divide properly. With the exception of monosomy X or Turner syndrome, monosomic embryos are uni-formly miscarried (Chapter 36). Most trisomic fetuses are also miscarried; only three (trisomy 13, 18 and 21) are reported among live births. Those that survive to birth are likely mosaics that carry non affected cell lineages. If all the chromosomes are present in multiples other than 2n, the embryo or fetus is polyploid.
Although it is critical that the zygote has 2n chromosomes, it is also important that one set of chromosomes comes from each parent. Dermoid cysts and hydatidiform moles (gestational trophoblastic disease; Chapter 45) each have all 46 chromosomes from a single parent. Cytogenetic studies of these entities have shown the importance of imprinting in early embryonic development. Imprinting is the process by which specific genes are methylated so that they can no longer be transcribed. Normal embryonic development requires that one set of genes be maternally imprinted and a second paternally. Otherwise, important steps in development will not occur and the zygote cannot form normally. For instance, two sets of maternally imprinted genes are present in dermoid tumors of the ovary, resulting in development of disorganized fetal tissues without any supporting placenta or fetal membranes. Conversely, two sets of paternally imprinted genes are present in hydatidiform moles. In these cases, dysplastic trophoblast develops, but a fetus does not.