Biology Reference
In-Depth Information
segregation of chromosome homologs is completed in the first meiotic division
(meiosis I) and the segregation of chromatids is completed in the second meiotic
division (meiosis II), ultimately producing haploid gametes. The mechanism,
regulation, and checkpoint functions of meiosis II chromatid segregation appear
similar to the well-defined processes associated with mitosis.
10
In contrast,
meiosis I requires suppression of the tendency to segregate sister chromatids
and instead the homologous chromosomes are separated. More than 50% of all
spontaneous miscarriages are due to errors in chromosome segregation (nondis-
junction) at the first meiotic division.
11
Moreover, 90% of Down syndrome cases
can be attributed to errors in maternal meiosis.
12
With few exceptions, the
critical meiosis genes appear identical in all eukaryotes.
13,14
The pairing of homologous chromosomes in meiosis I is a complex process
fraught with many pitfalls that may ultimately result in infertility. Homologous
chromosome pairing is initiated in Prophase I by the SPO11 gene product,
14,15
which
actively
introduces
hundreds
of DSBs into the sister chromatids.
16
The
homologous recombination (HR) repair of these DSBs by the nearest sister is
suppressed by the formation of meiosis-specific lateral elements between the
chromatids.
17
This leaves the homologous chromosome as the only DNA se-
quences available for HR repair to restore the exact integrity of the genome
(
Fig. 1
). The DSBs are first resected by a 5
0
!
3
0
exonuclease.
18,19
The resulting
3
0
single-stranded DNA (ssDNA) end is then used in a classic homologous pairing
and strand invasion reaction with the chromosome homolog to form a D-loop.
Strand invasion requires RAD51 and/or the meiosis-specific DMC1, which are
homologs to the prototypical bacterial recombination-initiation protein RecA.
20,21
The ssDNA-binding (SSB) protein, replication protein A (RPA), is an essential
cofactor in this process.
22,23
Mutation of SPO11 or RAD51 results in a dramatic
reduction of homologous chromosome pairing, a high frequency of meiosis I
nondisjunction, and gamete inviability. In mice, more than 400 DSB sites are
formed that contain RAD51 and RPA beginning in leptotene.
24
That the DSBs are
almost always faithfully repaired is a testament to the accuracy and dependability
of the process in the preservation of the many sexual species on earth.
Approximately 90% of the DSB sites are resolved following repair in a
process that converts one parental homolog DNA sequence to the other
parental homolog sequence with concurrent loss of that parental homolog
DNA sequence (gene conversion; Ref.
25
). These events leave the remaining
chromosome of both parents intact.
25
The remaining 10% (40-50 in human)
introduce visible chromosomal crossovers known as chiasmata, which exchange
entire arms of genetic information reciprocally from one parental chromosome
to the other.
26
Ultimately, there are two significant events associated with meiotic
DSB repair: (1) genetic information is exchanged between chromosomes, which
is the basis of modern genetics,
27
and (2) homologous chromosomes become
linked via
chiasmata
that are essential for proper chromosome segregation.
