Sex Determination and Sex Chromosomes PDF

Sex determination and Sex chromosomes Raihana M. Abdulhamid, RMT Learning Objectives At the end of the lecture, the students should be able to: 1. Explain how genes on the sex chromosomes are inherited 2. Explain the mechanism of X inactivation 3. Examine how sex influences gene expression ...

Sex determination and Sex chromosomes Raihana M. Abdulhamid, RMT Learning Objectives At the end of the lecture, the students should be able to: 1. Explain how genes on the sex chromosomes are inherited 2. Explain the mechanism of X inactivation 3. Examine how sex influences gene expression Sex Determination SPOT CHECK! The last pair of human chromosomes, are known as? Sex can be controlled by: Ploidy of an individual Allelic mechanisms in which sex is determined by a single allele or multiple alleles Environmental factors Sex chromosomes XY System Within the normal 23 pairs of human chromosomes, one pair was shown to vary in males & females. These two chromosomes were designated the X & Y chromosomes. The human females has two X chromosomes. The human male has one X and one Y chromosome. SPOT CHECK! Between the two sex chromosomes, which influences the immature gonads to become testis? The X and Y Chromosomes Role in Sexual Differentiation Genetic sex is established at the time of fertilization and is dependent on whether an X- or Y-bearing sperm fertilizes the X-bearing egg. Gonadal sex, the type of gonads that develop, is determined by the sex chromosome complement (XX or XY) and sex-determining genes. Role in Sexual Differentiation Before the seventh week of embryonic life, the gonads of both sexes appear identical. Under the influence of the Y chromosome, the immature gonad becomes a testis. In the absence of the Y chromosome and with two normal X chromosomes, the gonad differentiates into an ovary. Role in Sexual Differentiation Before the seventh week of embryonic life, the gonads of both sexes appear identical. Under the influence of the Y chromosome, the immature gonad becomes a testis. In the absence of the Y chromosome and with two normal X chromosomes, the gonad differentiates into an ovary. Role in Sexual Differentiation Before the seventh week of embryonic life, the gonads of both sexes appear identical. Under the influence of the Y chromosome, the immature gonad becomes a testis. In the absence of the Y chromosome and with two normal X chromosomes, the gonad differentiates into an ovary. Pseudoautosomal Regions Distal region of the p arms of the X and Y chromosomes contains highly similar DNA sequences. ○ Normal meiosis in the male, crossing-over occurs between these regions. ○ Resembles the crossing-over in autosomes, hence it is termed pseudoautosomal region or PAR1. PAR2, a region of homology is at the distal ends of Xq and Yq, which has been observed to associate during male meiosis, with proven recombination events. PAR1 is 2.6 Mb and contains at least 24 genes, whereas PAR2 is only 320 kb and has 4 genes. Pseudoautosomal Regions SPOT CHECK! What is the region located at the distal ends of the long arms of X & Y chromosomes ? X Chromosome Dosage Compensation, Lyon Hypothesis & Mechanism of X Inactivation SPOT CHECK! Who developed the Lyon hypothesis ? X Chromosome The presence of two X chromosomes in normal human females and one X in normal human males is unique compared with the equal numbers of autosomes present in the cells of both sexes It is possible to speculate that this disparity should create a genetic dosage problem. Dosage compensation Even though males inherit only one X chromosome, there is no disadvantage in the amount gene product their cells produce because females only have a single active X chromosome in each cell. If one of the two X chromosomes is inactive in the cells of females the dosage of genetic information that can be expressed in males and females is equivalent. The X inactivation is also termed, the Lyon hypothesis after its proponent, Dr. Mary Lyon Lyon Hypothesis/ X inactivation In 1961, the single active X chromosome mechanism of X-dosage compensation in mammals was developed by Mary Lyon and has been since known as the Lyon hypothesis. Lyon Hypothesis/ X inactivation In a given cell, when a female’s X chromosome becomes inactivated, it is converted into a Barr body. After inactivation, all the descendants of that cell will have the same chromosome inactivated. Barr bodies Sex chromatin body Inactivated X chromosome Susumo Ohno was the first to suggest that the Barr body arises from one of the two X chromosomes Provides a mechanism for dosage compensation If one of the two X chromosomes is inactive in the cells of females the dosage of genetic information that can be expressed in males and females is equivalent. Barr body Mechanism of X-chromosome Inactivation A gene that controls X inactivation is XIST (X-inactive-specific transcript) It is located at the X-inactivation center (XIC) at band Xq13 Only the inactive X expresses this gene. XIST encodes a large molecule of RNA (XIST RNA) Mechanism of X-chromosome Inactivation XIST RNA accumulates along the X chromosome containing the active XIST gene and proceeds to inactivate all (or almost all) of other genes on that chromosome Barr bodies are inactive chromosomes “painted” with XIST RNA. Mechanism of X-chromosome Inactivation SPOT CHECK! What happens to the X chromosome of a female after it is inactivated? SPOT CHECK! A gene that controls X inactivation Y Chromosome Y Chromosome ❖ Made up of several different regions: Pseudoautosomal regions at the distal p and q arm, PAR1 and PAR2 Heterochromatic region on the q arm Male Specific Region of the Y (MSY) located between PAR1 and PAR2 with 78 protein-coding genes that encode 27 distinct proteins 12 of the MSY genes are expressed in many organs throughout the body, while 11 MSY genes are expressed predominantly in the testes. Y Chromosome ❖ Made up of several different regions: Pseudoautosomal regions at the distal p and q arm, PAR1 and PAR2 Heterochromatic region on the q arm Male Specific Region of the Y (MSY) located between PAR1 and PAR2 with 78 protein-coding genes that encode 27 distinct proteins 12 of the MSY genes are expressed in many organs throughout the body, while 11 MSY genes are expressed predominantly in the testes. Y Chromosome Azoospermia factor ( AZF ) - A gene controlling spermatogenesis, was first Testis-determining factor proposed by Tiepolo and Zuffardi (TDF) in 1976 and mapped to the distal part of the euchromatic Yq11 Gene SRY region. (sex-determining region Y) Y Chromosome Azoospermia factor ( AZF ) Testis-determining factor - leads to differentiation of the (TDF) indifferent gonads into testes, located on the short arm of the Y chromosome Gene SRY (sex-determining region Y) Y Chromosome Azoospermia factor ( AZF ) Testis-determining factor (TDF) Gene SRY (sex-determining region Y) - It is located on the short arm of the Y at band p11.3 in the MSY region Y Chromosome Azoospermia factor ( AZF ) Testis-determining factor (TDF) Gene SRY (sex-determining region Y) SPOT CHECK! A region located between PAR 1 and PAR 2 Sex Chromosomes Abnormalities Sex Chromosomes Abnormalities Can be numerical or structural Present in all cells or in mosaic form X & Y chromosome aneuploidy is relatively common Structural abnormalities are less common Mosaicism is more common for sex chromosome abnormalities than autosomal abnormalities SPOT CHECK! 45,X is also known as? Numerical Abnormalities of the Sex Chromosomes 45,X Turner Syndrome (45,X) 45,X (and its variants) occurs in approximately 1 in 2,500 live-born females One of the most common chromosome abnormalities in spontaneous abortions 75% of patients with 45,X, the X chromosome is maternal in origin. Turner Syndrome Phenotype Clinical features in newborns may include: ❏ decreased mean birth weight ❏ posteriorly rotated ears ❏ neck webbing ❏ edema of hands and feet Turner Syndrome Phenotype Most older children and adults have ❏ short stature and ovarian failure ❏ variable dysmorphic features: ❏ down-slanting eyes ❏ posteriorly rotated ears ❏ low posterior hairline ❏ webbed neck ❏ a broad chest ❏ short fourth metacarpals, ❏ cubitus valgus Turner Syndrome Development Infants can have feeding problems and developmental delay. Problems with visual-spatial skills, working memory, executive functions, and social skills can occur. Turner Syndrome NORMAL FEMALE WITH TURNER’S SYNDROME Numerical Abnormalities of the Sex Chromosomes 47, XXX Trisomy X (47,XXX) Trisomy X or triple X is the most frequent sex chromosome disorder present at birth in females, occurring in 1 in approximately 1,000 live female birth It was termed “superfemale”, but gives a misconception of the syndrome and is no longer in use Trisomy X Origin Conceptions result from maternal nondisjunction at meiosis I. Two of the X chromosomes are inactivated, and abnormalities could result from three active X chromosomes early in embryonic development, prior to X inactivation and/or from genes on the X chromosome that escape inactivation. Trisomy X Phenotype In contrast to the result of a 45,X karyotype, there is not a recognizable syndrome in females. Pubertal development is normal normal fertility small number have ovarian dysfunction and premature ovarian insufficiency sometimes associated with autoimmune thyroid Trisomy X Development Females have normal intelligence, but most have lower IQs than their siblings. Risk for mild to moderate developmental problems in the areas of motor, speech and language, and learning. Trisomy X SPOT CHECK! Old term for 47,XXX but is no longer used. Numerical Abnormalities of the Sex Chromosomes Variants with Additional X Chromosomes SPOT CHECK! Sex chromosome abnormality that can cause infertility in men? Variants with Additional X Chromosomes 48,XXXX 49,XXXXX 47,XXY (Klinefelter Syndrome) Klinefelter Syndrome (47,XXY) First sex chromosome disorder to be described and its cytogenetic cause identified Most common cause of hypogonadism and infertility in males Klinefelter Syndrome Origin Extra chromosome arose at: ➔ paternal meiosis I (53% of patients) ➔ maternal meiosis I (34%) ➔ maternal meiosis II (9% ) ➔ from postzygotic errors (3%) Klinefelter Syndrome Phenotype Taller than average stature Eunuchoid build with long limbs and pear-shaped hips Testicular and penile size is usually small during childhood Gynecomastia occurs in up to 50% of males during adolescence Klinefelter Syndrome Phenotype Testes are small in adulthood Hypergonadotropic hypogonadism Almost all have infertility Absent spermatogenesis Tubular hyalinization Leydig cell hyperplasia. Most are born with spermatogonia Klinefelter Syndrome Development Boys have been reported to have decreased muscle tone during infancy, delayed speech and language skills, and an increased incidence of reading disability and dyslexia. Klinefelter Syndrome (47,XXY) Numerical Abnormalities of the Sex Chromosomes Variants with Additional X or Y Chromosomes Variants with Additional X or Y Chromosomes 48,XXYY 48,XXXY 49,XXXXY 49, XXXYY 47, XYY 47,XYY One in 800–1,000 males has an extra Y Origin chromosome. This arises through nondisjunction at paternal meiosis II. 47,XYY Severe facial acne Phenotype Tall and thin Good general health Sexual orientation is typically heterosexual Most have normal fertility and are able to father children 47,XYY Intelligence is normal, although there is Development an increased incidence of learning disabilities. Delays in speech and language development occur in some boys. An increased rate of autism spectrum disorder in boys Hyperactive behavior, distractibility, temper tantrums, and a low frustration tolerance in late childhood and early adolescence 47,XYY Numerical Abnormalities of the Sex Chromosomes Variants with Additional Y Chromosomes Variants with Additional Y Chromosomes 48,XYYY 49,XYYYY SPOT CHECK! Determine the abnormality. Structural Abnormalities of the Sex Chromosomes X Chromosome Isochromosome Xq commonly found in patients with Turner syndrome Involved in translocations, both balanced and unbalanced Deletions and duplications X Chromosome Isochromosome X - An isochromosome, consisting of two copies of the long arm (missing all or most of the short arm), as a single cell line or, more commonly, in mosaicism with a 45,X cell line. Y chromosome Lead to deletion of the proximal long arm might be associated with azoospermia, infertility, and short stature. Marker chromosomes are important to detect due to the risk of gonadoblastoma in females with Turner syndrome. FISH probes and chromosome microarray identify marker Y chromosomes. Thank you for your attention! Reference: Gersen, S. and Keagle, M. (2013) The Principles of Clinical Cytogenetics. 3rd Edition.