Added: Ameka Bruch - Date: 17.02.2022 05:21 - Views: 18298 - Clicks: 560
Try out PMC Labs and tell us what you think. Learn More. Fundamental differences exist between males and females, encompassing anatomy, physiology, behaviour, and genetics. Such differences undoubtedly play a part in the well documented, yet poorly understood, disparity in disease susceptibility between the sexes. Although traditionally attributed to gonadal sex hormone effects, recent work has begun to shed more light on the contribution of genetics — and in particular the sex chromosomes — to these sexual dimorphisms. Here, we explore the accumulating evidence for a ificant genetic component to mammalian sexual dimorphism through the paradigm of sex chromosome evolution.
The differences between the extant X and Y chromosomes, at both a sequence and regulatory level, arose across million years. A functional result of these differences is cell autonomous sexual dimorphism. By understanding the process that changed a pair of homologous ancestral autosomes into the extant mammalian X and Y, we believe it easier to consider the mechanisms that may contribute to hormone-independent male—female differences. We highlight key roles for genes with homologues present on both sex chromosomes, where the X-linked copy escapes X chromosome inactivation.
Finally, we summarise current experimental paradigms and suggest areas for developments to further increase our understanding of cell autonomous sexual dimorphism in the context of health and disease. Men and women differ in their physical appearance, indicative of an anatomical and physiological sexual dimorphism that is widespread in the natural world . In primates, for example, males of Gorilla and Mandrillus taxa species are ificantly larger than females; in contrast, females are generally larger than males in the Lorisid and Cheirogalid taxa .
Ultimately such differences must be attributed to male—female variation at the genetic level, which in turn drives the development of the gon, and production of gonadal sex hormones in utero. Prior to this point of physiological differentiation, though, the sex chromosomes have already induced sex-specific aspects of organ development in the absence of gonadal sex hormones 3 , 4. Subsequently, however, as mammals and their gon do not each exist in isolation, these two variables must be separated in order to further understand their relative contributions to sexual dimorphism in human health and disease.
In this review, we seek first to highlight some of the key evidence of human sexual dimorphism. Subsequently, we use the evolution of the sex chromosomes as a paradigm with which to understand the possible sources of genetic sexual dimorphism in mammals. Finally, we summarise a small of the model systems available for investigating the mechanisms of mammalian genetic sexual dimorphism. The difference in disease prevalence rates between males and females has been recognised for many years, with examples from cradle to grave.
Boys are more likely to be born with pyloric stenosis or malformations of the genitourinary tract, whereas girls are more likely to have developmental dysplasia of the hip or scoliosis 5 , 6. In early childhood, boys have a higher incidence of bacterial and viral infections, including meningitis, septicaemia, influenza A and respiratory syncytial viruses 7 , 8 , 9 , Although these associations have been shown to be reproducible, the underlying mechanisms are yet to be definitively elucidated.
The most prominent two hypotheses attribute these sexual dimorphisms to either the gonadal sex hormones or the sex chromosomes. Both male and female human fetuses are exposed to high levels of maternal oestrogens in utero , in addition to hormones produced by the placenta . Furthermore, males start producing testosterone following testis determination at around eight weeks gestation . Subsequently, girls enter puberty slightly earlier than boys, and both sexes achieve maximum sex hormone levels during their mid-teens.
In later life, from around the age of 50, testosterone levels in men drop gradually, whereas oestrogen levels in women fall precipitously during menopause . A of diseases have been associated with these sex-specific patterns of hormone secretion.
For example, boys have a high prevalence of asthma in the pre-pubertal years . Following puberty, when testosterone production is markedly increased, the burden of disease is ificantly reduced. In contrast, the prevalence of asthma during childhood in girls is low, but this increases ificantly during puberty, as does the risk of severe asthma .
Interestingly, there is a subsequent drop in asthma severity in women aged 50—65, correlating with the timing of menopause and reduced oestrogen production . Post-menopausal women are also at increased risk of developing cardiovascular disease, which has similarly been attributed to reduced oestrogen levels .
The endocrine system therefore appears to play a ificant role in mediating some sexual dimorphisms in disease. However, with our ever-increasing understanding of sex chromosomes, it has become clear that some of the differences between males and females are due to genetics. Genetic testis determination triggered the evolution of the mammalian sex chromosomes, producing a pair of chromosomes fundamentally different from the autosomes in terms of gene content, regulation of gene expression, and inheritance.
The extant X and Y chromosomes, and the females and males in which they exist, also differ from each other as a result of this process. We can therefore use the evolution of the sex chromosomes as a paradigm for understanding possible genetic mechanisms underlying male—female differences. The mammalian sex chromosomes have evolved from a pair of autosomes during the past million years Figure 1 A 23 , Between and million years ago, mutations on the proto-Y chromosome resulted in the creation of the testis-determining gene SRY : carriers of SRY develop with testes, while non-carriers develop with ovaries 25 , SRY -based genetic testis determination is conserved in most eutherian mammals, and the sequence is present in metatherians  , though whether it retains a role in testis determination in this mammalian clade remains an open question.
A A testis-determining locus proto- SRY , white was acquired on an autosome around — million years ago. Sexually antagonistic alleles orange then evolved at nearby loci, selected for in males due to their tight linkage to SRY. Recombination suppression between the proto-X and -Y chromosomes likely followed on from chromosomal inversions grey , which were subsequently only carried by males. Over evolutionary time, the lack of sexual recombination led to the appearance of repetitive DNA sequences and short-term expansion.
In the longer term, large deletions took place. The outcome of this process is the small, relatively gene poor Y chromosome observed in most eutherian mammals today. Concurrent with this process, X upregulation XUR evolved to balance X gene dosage between the single X chromosome and the autosomes in males: this is depicted as the doubled surface area of the X chromosomes in C compared to B. This is depicted as the loss of colour of the X chromosome. Abbreviations: Xa, active X chromosome; Xi, inactive X chromosome.
After the acquisition of SRY , the proto-Y chromosome picked up a of male-beneficial mutations. As a result of linkage with the testis-determining locus, these mutations provided the selective force to suppress recombination between proto-X and proto-Y .
Mechanistically, the suppression and eventual elimination of recombination was possibly achieved by a series of local inversions . Non-recombining regions also accumulated deleterious mutations that could not be repaired. Over evolutionary time, lack of recombination led to the accrual of repetitive DNA sequences and a short-term increase in the size of the chromosome, though this eventually resulted in large deletions and explains the relatively diminutive size of the Y chromosome in many mammals 28 , Most genes from the ancestral autosome pair were therefore lost from the Y chromosome, whereas the X chromosome largely maintained its gene content 23 , 27 , Taking humans as an example, the extant Y chromosome encodes fewer than 78 proteins; in contrast, the X chromosome contains around genes .
As a result of the evolution of XY testis determination, female mammals carry two copies of the relatively gene-rich X chromosome, whereas male mammals carry a single copy of the X chromosome and a gene-poor Y chromosome. The difference in X-linked gene dosage between males and females led to the appearance of compensation mechanisms aiming, firstly, to balance X expression with that of the autosomes and, secondly, to balance X expression between the homogametic XX and heterogametic XY sexes.
However, XUR alone would leave females expressing X genes at twice the level of autosomal genes. In order to correct this X:autosome imbalance, a further step is the inactivation of one X chromosome in the homogametic sex two of the same sex chromosomes — X chromosome inactivation XCI, Figure 1 D. In female human embryos, XCI is random, resulting in the silencing of either the maternally derived Xm or paternally derived X chromosome Xp in each cell 32 , Subsequently, a of other mechanisms lock-in the inactive state, including the histone modification H3K27 tri-methylation 38 , 39 , DNA methylation 40 , 41 , 42 , and a shift in replication timing relative to the rest of the nucleus 43 , The X chromosome has the potential to cause differences between males and females in a of ways.
Secondly, a of genes escape XCI and are thus expressed from both X chromosomes. These genes are therefore more highly expressed in XX females compared to XY males, resulting in further potential for cell autonomous sexual dimorphism. Thirdly, the parental origin of the X chromosome in males and females is not equivalent, and differential gene expression between the sexes could result from genomic imprinting. A well-known representation of this phenomenon is the tortoiseshell cat, which is a mosaic of black and orange X-linked coat colours .
X chromosome mosaicism has long been recognised as a way in which individuals with two X chromosomes differ from those with a single X chromosome, both in terms of normal physiology and disease . Any subtle difference in function between the two alleles could therefore manifest as sexual dimorphism Figure 2. ificant differences in function present as X-linked disease. In males, the presence of a single X chromosome means that X-linked recessive mutations have a fully-penetrant phenotype, but in females this is usually mild or not clinically apparent.
X-linked diseases present a range of phenotypes, from relatively benign colour blindness  , through life-limiting Duchenne and Becker muscular dystrophies  , to embryonic lethality, as in incontinentia pigmenti . Possible mechanisms underlying male—female genetic sexual dimorphism in eutherian mammals. The organism-wide expression of an individual gene allele is represented by block colour, with XY males in the left-hand column and XX females in the right-hand column. B XCI skewing can result in a change to the percentage of cells expressing any given X allele in females.
C As both alleles of XCI escapee genes are expressed in females, the relative expression is increased compared to males. E Ubiquitously expressed Y-linked genes are only present in males. Abbreviations: Xm, maternally derived X chromosome; Xp, paternally derived X chromosome.
Gene expression is depicted in arbitrary units, taking 1 as normal expression for a single chromosome. Occasionally females also have a typically male disease phenotype, denoted as manifesting heterozygosity. In these individuals, XCI is no longer random, and a skew is present. Such a skew can be classified as either primary, if it arose at the onset of XCI, or secondary if it arose later .
There is abundant evidence for the existence of primary skewing in mouse, resulting from the influence of a locus denoted the X controlling element Xce. Cattanach observed that certain mouse strains have stronger Xces, such that the X chromosomes carrying these Xces are more likely to remain active in F1 hybrid crosses .
In humans, there is little evidence for either the presence of an Xce or primary skewing. Some studies have suggested there may be a genetic component to XCI choice, i. Secondary skewing has been observed at a population level in humans .
In a situation where no primary skew is present, two populations of cells will exist in an XX female: each expressing either the Xm or Xp allele of any given X-linked gene Figure 2. Each of these alleles may differentially affect cellular growth, such that the rate of proliferation varies between the two populations, and a competition ensues . The cell population with the growth advantage will outgrow the other — usually, but not always, the normal and mutant alleles, respectively 46 , Based on evidence in the literature, it is likely that this secondary skewed XCI is largely tissue-specific, and is common in normal, healthy individuals 53 , Skewed XCI has also been proposed as one of the causes underlying the female sex bias in autoimmune disease, and in this context it is known as the loss of mosaicism hypothesis .
A of X-linked genes are not silenced by XCI, and could therefore effect male—female differences in expression Figure 2. Some of these genes are located within the pseudoautosomal region PAR , and others have been found outside this region. This homology enables X—Y pairing, synapsis, and recombination during meiosis 59 , 60 , As males and females have PAR genes in equal copy , it was expected that expression levels would be equivalent between the sexes.
However, recent work indicates the existence of a male expression bias in humans . This bias likely from XCI spreading into the PAR on the inactive X Xi in females, but increased expression from the Y-linked genes in males could also contribute. The PAR is perhaps one of the most poorly studied genomic regions in sequenced eutherian mammals, as the assembly quality is not equivalent to the rest of the genome. Further work may build upon the recently reported male expression bias to reveal an unexpected role for the PAR in mammalian sexual dimorphism.
The disparity in constitutive escape genes between human and mouse has been attributed to the arrangement of the genes on the chromosome. In mouse, escapees are situated in blocks of only one or two genes, whereas in human these blocks contain 10—15 genes . Even within species, though, the process has inherent variability, creating the potential for sexually dimorphic effects. For the remainder, inter-tissue variability in XCI-escape was observed.
There was also ificant variability in Xi gene expression between the two X chromosome haplotypes within an individual. Furthermore, escapee expression from the Xi was on average only one-third of the level of expression from the active X Xa .
Importantly, 52 of the 67 non-PAR escape genes showed female-biased expression. Taken together, these data suggest that the process of XCI-escape is tightly regulated for some genes and highly variable for others. This may reflect absolute limits on gene dosage for tightly regulated genes and flexibility of expression for those showing variability. The outcomes following XCI, i. More work will be required to elucidate whether expression bias at the RNA level translates into phenotypic sexual dimorphism at the organism level.
Further evidence of the role of escape genes in sexual dimorphism has emerged from studies of human cancers.Lady looking sex Chromo
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