Crossing Over
Crossing over, or recombination, is the exchange of chromosome segments between nonsister chromatids in meiosis. Crossing over creates new combinations of genes in the gametes that are not found in either parent, contributing to genetic diversity.
Homologues and Chromatids
All body cells are diploid, meaning they contain pairs of each chromosome. One member of each pair comes from the individual's mother, and one from the father. The two members of each pair are called homologues. Members of a homologous pair carry the same set of genes, which occur in identical positions along the chromosome. The specific forms of each gene, called alleles, may be different: One chromosome may carry an allele for blue eyes, and the other an allele for brown eyes, for example.
Meiosis is the process by which homologous chromosomes are separated to form gametes. Gametes contain only one member of each pair of chromosomes. Prior to meiosis, each chromosome is replicated. The replicas, called sister chromatids, remain joined together at the centromere. Thus, as a cell starts meiosis, each chromosome is composed of two chromatids and is paired with its homologue. The chromatids of two homologous chromosomes are called nonsister chromatids.
Meiosis occurs in two stages, called meiosis I and II. Meiosis I separates homologues from each other. Meiosis II separates sister chromatids from each other. Crossing over occurs in meiosis I. During crossing over, segments are exchanged between nonsister chromatids.
Mechanics of Crossing Over
The pairing of homologues at the beginning of meiosis I ensures that each gamete receives one member of each pair. Homologues contact each other along much of their length and are held together by a special protein structure called the synaptonemal complex. This association of the homologues may persist from hours to days. The association of the two chromosomes is called a bivalent, and because there are four chromatids involved it is also called a tetrad. The points of attachment are called chiasmata (singular, chiasma).
The pairing of homologues brings together the near-identical sequences found on each chromosome, and this sets the stage for crossing over. The exact mechanism by which crossing over occurs is not known. Crossing over is controlled by a very large protein complex called a recombination nodule. Some of the proteins involved also play roles in DNA replication and repair, which is not surprising, considering that all three processes require breaking and reforming the DNA double helix.
One plausible model supported by available evidence suggests that crossing over begins when one chromatid is cut through, making a break in the double-stranded DNA (recall that each DNA strand is a double helix of nucleotides). A nuclease enzyme then removes nucleotides from each side of the DNA strand, but in opposite directions, leaving each side with a single-stranded tail, perhaps 600 to 800 nucleotides long.
One tail is then thought to insert itself along the length of one of the nonsister chromatids, aligning with its complementary sequence (i.e., if the tail sequence is ATCCGG, it aligns with TAGGCC on the nonsister strand). If a match is made, the tail pairs with this strand of the nonsister chromatid. This displaces the original paired strand on the nonsister chromatid, which is then freed to pair with the other single-stranded tail. The gaps are filled by a DNA polymerase enzyme . Finally, the two chromatids must be separated from each other, which requires cutting all the strands and rejoining the cut ends.
The Consequences of Crossing Over
A chiasma occurs at least once per chromosome pair. Thus, following crossing over, at least two of the four chromatids become unique, unlike those of the parent. (Crossing over can also occur between sister chromatids; however, such events do not lead to genetic variation because the DNA sequences are identical between the chromatids.) Crossing over helps
to preserve genetic variability within a species by allowing for virtually limitless combinations of genes in the transmission from parent to off-spring.
The frequency of recombination is not uniform throughout the genome. Some areas of some chromosomes have increased rates of recombination (hot spots), while others have reduced rates of recombination (cold spots). The frequency of recombination in humans is generally decreased near the centromeric region of chromosomes, and tends to be greater near the telomeric regions. Recombination frequencies may vary between sexes. Crossing over is estimated to occur approximately fifty-five times in meiosis in males, and about seventy-five times in meiosis in females.
X-Y Crossovers and Unequal Crossovers
The forty-six chromosomes of the human diploid genome are composed of twenty-two pairs of autosomes, plus the X and Y chromosomes that determine sex. The X and Y chromosomes are very different from each other in their genetic composition but nonetheless pair up and even cross over during meiosis. These two chromosomes do have similar sequences over a small portion of their length, termed the pseudoautosomal region, at the far end of the short arm on each one.
The pseudoautosomal region behaves similarly to the autosomes during meiosis, allowing for segregation of the sex chromosomes. Just proximal to the pseudoautosomal region on the Y chromosome is the SRY gene (sex-determining region of the Y chromosome), which is critical for the normal development of male reproductive organs. When crossing over extends past the boundary of the pseudoautosomal region and includes this gene, sexual development will most likely be adversely affected. The rare occurrences of chromosomally XX males and XY females are due to such aberrant crossing over, in which the Y chromosome has lost—and the X chromosome has gained—this sex-determining gene.
Most crossing over is equal. However, unequal crossing over can and does occur. This form of recombination involves crossing over between nonallelic sequences on nonsister chromatids in a pair of homologues. In many cases, the DNA sequences located near the crossover event show substantial sequence similarity. When unequal crossing over occurs, the event leads to a deletion on one of the participating chromatids and an insertion on the other, which can lead to genetic disease, or even failure of development if a crucial gene is missing.
Crossing Over as a Genetic Tool
Recombination events have important uses in experimental and medical genetics. They can be used to order and determine distances between loci (chromosome positions) by genetic mapping techniques. Loci that are on the same chromosome are all physically linked to one another, but they can be separated by crossing over. Examining the frequency with which two loci are separated allows a calculation of their distance: The closer they are, the more likely they are to remain together. Multiple comparisons of crossing over among multiple loci allows these loci to be mapped, or placed in relative position to one another.
Recombination frequency in one region of the genome will be influenced by other, nearby recombination events, and these differences can complicate genetic mapping. The term "interference" describes this phenomenon. In positive interference, the presence of one crossover in a region decreases the probability that another crossover will occur nearby. Negative interference, the opposite of positive interference, implies that the formation of a second crossover in a region is made more likely by the presence of a first crossover.
Most documented interference has been positive, but some reports of negative interference exist in experimental organisms. The investigation of interference is important because accurate modeling of interference will provide better estimates of true genetic map length and intermarker distances, and more accurate mapping of trait loci. Interference is very difficult to measure in humans, because exceedingly large sample sizes, usually on the order of three hundred to one thousand fully informative meiotic events, are required to detect it.
see also DNA Polymerases; DNA Repair; Linkage and Recombination; Meiosis; Mendel, Gregor.
Marcy C. Speer
Bibliography
Strachan, Tom, and Andrew P. Read. Human Molecular Genetics. New York: Wiley-Liss, 1996.
