WHO laboratory manual for the examination and processing of human semen

Human sex chromosomes evolved from autosomes. Nineteen ancestral autosomal genes persist as differentiated homologs on the X and Y chromosomes. The ages of individual X-Y gene pairs (measured by nucleotide divergence) and the locations of their X members on the X chromosome were found to be highly correlated. Age decreased in stepwise fashion from the distal long arm to the distal short arm in at least four "evolutionary strata." Human sex chromosome evolution was probably punctuated by at least four events, each suppressing X-Y recombination in one stratum, without disturbing gene order on the X chromosome. The first event, which marked the beginnings of X-Y differentiation, occurred about 240 to 320 million years ago, shortly after divergence of the mammalian and avian lineages.

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Four Evolutionary Strata on the Human X Chromosome

Trisomic and monosomic (aneuploid) embryos account for at least 10% of human pregnancies and, for women nearing the end of their reproductive lifespan, the incidence may exceed 50%. The errors that lead to aneuploidy almost always occur in the oocyte but, despite intensive investigation, the underlying molecular basis has remained elusive. Recent studies of humans and model organisms have shed new light on the complexity of meiotic defects, providing evidence that the age-related increase in errors in the human female is not attributable to a single factor but to an interplay between unique features of oogenesis and a host of endogenous and exogenous factors.

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Human aneuploidy: mechanisms and new insights into an age-old problem

https://www.fertstert.org/article/S0015-0282(00)01679-4/pdf

Effects of male age on semen quality and fertility: a review of the literature

Aneuploidy is the most common chromosome abnormality in humans, and is the leading genetic cause of miscarriage and congenital birth defects. Since the identification of the first human aneuploid conditions nearly a half-century ago, a great deal of information has accrued on its origin and etiology. We know that most aneuploidy derives from errors in maternal meiosis I, that maternal age is a risk factor for most, if not all, human trisomies, and that alterations in recombination are an important contributor to meiotic non-disjunction. In this review, we summarize some of the data that have led to these conclusions, and discuss some of the approaches now being used to address the underlying causes of meiotic non-disjunction in humans.

The origin of human aneuploidy: Where we have been, where we are going

The frequency and distribution of aneuploidy was compared in 11,615 karyotyped human sperm and 772 karyotyped human oocytes to determine if all chromosomes are equally likely to be involved in aneuploid events or if some chromosomes are particularly susceptible to nondisjunction. The frequency of hypohaploidy and hyperhaploidy was compared among different chromosome groups and individual chromosomes for human sperm and oocytes. In general, hypohaploid chromosome complements were more frequent than hyperhaploid complements, in sperm and oocytes. The distribution of chromosome loss in the hypohaploid complements indicated that significantly fewer of the large chromosomes and significantly more of the small chromosomes were lost, suggesting that technical loss predominantly affects small chromosomes. A conservative estimate of aneuploidy (2 X hyperhaploidy) was approximately 3-4% in the human sperm and 18-19% in human oocytes. All chromosome groups were represented among hyperhaploid human sperm and oocytes. For human sperm, the observed frequency of hyperhaploidy equaled the expected frequency based on the assumption that the frequency of nondisjunction is equal for all chromosome groups, with two exceptions: group G and the sex chromosomes. Among individual chromosomes in human sperm, chromosomes 1 and 21 and the sex chromosomes had a significant excess of hyperhaploidy. For human oocytes, there were fewer hyperhaploid oocytes than expected for chromosome groups C and F and more than expected for chromosome groups D and G. Among individual chromosomes there was a significant excess for chromosome 21. These results indicate that all chromosomes are susceptible to nondisjunction but that chromosome 21 is particularly prone to aneuploidy in both human sperm and oocytes. They also demonstrate that sex chromosome aneuploidy is common in human sperm but not in human oocytes.

Distribution of aneuploidy in human gametes: comparison between human sperm and oocytes.

We studied the frequencies of X- and Y-chromosome-bearing sperm, diploidy and disomy for chromosomes 1, 12, X, and Y in sperm from 10 normal men aged 21-52 years, to determine whether there was any relationship between donor age and any of these variables. Multicolor FISH was used to control for lack of probe hybridization and to distinguish diploid sperm from disomic sperm. A minimum of 10,000 sperm per donor was evaluated for each chromosome, for a total of 225,846 sperm studied. Sperm were considered disomic if two fluorescent signals were separated by a minimal distance of one signal domain. The mean frequencies of X- and Y-bearing sperm were 50.1% and 49.0%, respectively; not significantly different from 50%. There was no correlation between paternal age and "sex ratio" in sperm. Similarly, there was no association between the frequency of diploid sperm (mean, .16%; range, .06-.42%) and donor age. For disomy frequencies, there was no relationship between donor age and disomy 12 (mean, .16%; range, .10%-.25%), XX (mean, .07%; range, .03%-.17%), and XY sperm (mean, .16%; range, .08%-.24%). There was a significant increase in the frequency of YY sperm (P = .04; mean, .18%; range, .10%-.43%) and disomy 1 sperm (P = .01; mean, .11%; range, .05%-.18%) with donor age. In summary, our results do not support a correlation between paternal age and sex ratio or diploidy.

The relationship between paternal age, sex ratios, and aneuploidy frequencies in human sperm, as assessed by multicolor FISH

This review explores the relationship between sperm chromosomal constitution and morphology. With the advent of techniques for obtaining information on the chromosome complements of spermatozoa, this relationship has been studied in fertile men and in men with a high frequency of chromosomal abnormalities. Using human sperm karyotype analysis, no relationship between sperm chromosome abnormalities and morphology was found in fertile men, translocation carriers or post-radiotherapy cancer patients. Fluorescence in situ hybridization (FISH) analysis has not generally revealed a specific association between morphologically abnormal sperm and sperm chromosome abnormalities, but has indicated that teratozoospermia, like other forms of abnormal semen profiles (aesthenozoospermia, oligozoospermia) is associated with a modest increase in the frequency of sperm chromosome abnormalities. However, FISH studies on some infertile men and mouse strains have suggested that certain types of morphologically abnormal spermatozoa, such as macrocephalic multitailed spermatozoa, are associated with a very significantly increased frequency of aneuploidy. Thus, there may be an association between sperm morphology and aneuploidy in infertile men with specific abnormalities.

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Is there a relationship between sperm chromosome abnormalities and sperm morphology

Meiotic recombination is essential for the segregation of chromosomes and the formation of normal haploid gametes, yet we know very little about the meiotic process in humans. We present the first (to our knowledge) recombination maps for every autosome in the human male obtained by new immunofluorescence techniques followed by centromere-specific multicolor fluorescence in situ hybridization in human spermatocytes. The mean frequency of autosomal recombination foci was 49.8±4.3, corresponding to a genetic length of 2,490 cM. All autosomal bivalents had at least one recombination focus. In contrast, the XY bivalent had a recombination focus in 73% of nuclei, suggesting that a relatively large proportion of spermatocytes may be at risk for nondisjunction of the XY bivalent or elimination by meiotic arrest. There was a very strong correlation between mean length of the synaptonemal complex (SC) and the number of recombination foci per SC. Each bivalent presented a distinct distribution of recombination foci, but in general, foci were near the distal parts of the chromosome, with repression of foci near the centromere. The position of recombination foci demonstrated positive interference, but, in rare instances, foci were very close to one another.

Human male recombination maps for individual chromosomes.

Cigarette smoke contains chemi- cals which are capable of inducing aneuploidy in experimental systems. These chemicals have been shown to reach the male reproductive system, increasing oxidative DNA damage in human sperm and lowering semen quality. We have examined the association between smoking and aneuploid sperm by studying 31 Chinese men with similar demographic characteristics and lifestyle factors except for cigarette smoking. None of the men drank alcohol. These men were divided into three groups: nonsmokers (10 men), light smokers (<20 cigarettes/day, 11 men), and heavy smokers (20 cigarettes/day, 10 men). There were no significant differences in semen parameters or in age across groups. Two multi-color fluorescence in situ hybridizations (FISH) were performed: two-color FISH for chromosomes 13 and 21, and three-color FISH for the sex chromosomes using chromosome 1 as an internal autosomal control for diploidy and lack of hybridization. The mean hybridization efficiency was 99.78%. The frequency of disomy 13 was significantly higher in light and heavy smokers than in non- smokers, while no significant differences in the frequency of disomy 21, X or Y were observed across groups. Significant inter-donor heterogeneity in every category of disomic sperm examined was found in both light and heavy smokers, while in nonsmokers only XY disomy showed significant inter-donor differences. Thus, we conclude that cigarette smoking may increase the risk of aneuploidy only for certain chromosomes and that men may have different susceptibilities to aneuploidy in germ cells induced by cigarette smoking. Mol. Reprod. Dev. 59: 417- 421, 2001. fl 2001 Wiley-Liss, Inc.

Evelyn Ko

Papers

Distribution of aneuploidy in human gametes: comparison between human sperm and oocytes.

The relationship between paternal age, sex ratios, and aneuploidy frequencies in human sperm, as assessed by multicolor FISH

Is there a relationship between sperm chromosome abnormalities and sperm morphology

Human male recombination maps for individual chromosomes.

Cigarette smoking and aneuploidy in human sperm