Chromosomal Disorders & Sex Determination PDF

Chromosomal Disorders & Sex Determination BIO 130 LEC INTARMED 2030 | Prof. Bordallo/Leonardo | LU2 SEM 1 | SY. 2023-2024 TABLE OF CONTENTS VARIATION IN CHROMOSOME NUMBER I. Chromosomal Disorders A. Variation in Chromosome Number...

Chromosomal Disorders & Sex Determination BIO 130 LEC INTARMED 2030 | Prof. Bordallo/Leonardo | LU2 SEM 1 | SY. 2023-2024 TABLE OF CONTENTS VARIATION IN CHROMOSOME NUMBER I. Chromosomal Disorders A. Variation in Chromosome Number Euploidy a. Aneuploidy ➔ Presence of complete haploid sets of chromosomes (multiples of haploid number) b. Polyploidy ➔ Multiples of n B. Variation in Chromosome Structure a. Deletion b. Duplication c. Inversion d. Translocation II. Sex Determination A. Mammalian Pattern of Sex Determination a. Male Development b. Female Development c. Androgen Insensitivity Syndrome B. Genetic Mechanisms of Primary Sex Determination a. Transcription Factors b. Absence of Y Chromosome c. Presence of Y Chromosome C. Importance of Timing Figure 2: Terminology for Variation in Chromosome Numbers I. CHROMOSOMAL DISORDERS ANEUPLOIDY _______________________________________________________ Gain or loss of one or more chromosomes but not a complete set 2n ± x chromosomes Caused by nondisjunction ○ Failure of paired homologs or sister chromatids to separate during formation of gamete ○ First-division nondisjunction Occurs during first meiotic division ○ Second-division nondisjunction Occurs during second meiotic division Figure 1: Gene Location (Locus) in a Chromosome Stained chromosomes have characteristic banding patterns ○ Some parts of the chromosome stain lighter than others Lighter stains - not too condensed Darker stains - very condensed ○ Designated regions for specific location of genes Arms, regions, bands, and sub-band Figure 3: Meiotic Nondisjunction BIO 130 LEC LU 2 SEM 1 | IMED 2030 Page 1 of 10 SAMSON, SD; AGNES, NC; VITOR, GMZ; REYES, JCDC Chromosomal Disorders & Sex Determination BIO 130 LEC INTARMED 2030 | Prof. Bordallo/Leonardo | LU2 SEM 1 | SY. 2023-2024 Sex Chromosome Aneuploids in Humans Jacobs syndrome (47, XYY) Klinefelter syndrome - 47, XXY ➔ Presence of another Y chromosome Turner syndrome - 45, XO ➔ Normal looking except that they are unusually tall Triplo-X - 47, XXX ◆ Males are usually over 6 feet tall Jacobs syndrome - 47, XYY Autosomal Aneuploids in Humans Trisomy 21 - Down syndrome Trisomy 13 - Patau syndrome Trisomy 18 - Edwards syndrome Klinefelter syndrome (47, XXY) ➔ Total number of chromosomes: 47 ➔ Presence of more X chromosomes than Y chromosomes in male Figure 6: Karyotype of Jacobs syndrome Inactivation of the X chromosome early in embryonic development ○ Balances dose of X chromosome gene expression in males and females Figure 4: Karyotype and characteristics of Klinefelter ○ All X chromosomes, except one, are inactivated. syndrome In females: The other X chromosome is condensed all the time, thus, inactive. Turner syndrome (45, XO) ○ Around 15% of genes in the X chromosome escape ➔ Total number of chromosomes: 45 inactivation. ➔ Monosomy X ○ The inactivated X chromosome is called a sex ➔ Absence of an X chromosome in female chromatin body or Barr body. Normal female (XX) = 1 Barr body Normal male (XY) = no Barr body Turner (X0) = no Barr body Klinefelter (XXY) = 1 Barr body Triplo-X (XXX) = 2 Barr bodies Figure 5: Karyotype and characteristics of Turner syndrome Trisomy X/ Triplo-X (47, XXX) ➔ Usually normal ➔ Other cases: ◆ Underdeveloped secondary sex characteristics ◆ Sterility Figure 7: Barr body ◆ Delayed development of language and motor skills ◆ Mental retardation BIO 130 LEC LU 2 SEM 1 | IMED 2030 Page 2 of 10 SAMSON, SD; AGNES, NC; VITOR, GMZ; REYES, JCDC Chromosomal Disorders & Sex Determination BIO 130 LEC INTARMED 2030 | Prof. Bordallo/Leonardo | LU2 SEM 1 | SY. 2023-2024 Down syndrome (Trisomy 21) Patau syndrome (47, 13+) ➔ Prominent epicanthic fold, flat face, round head, ➔ Also known as Trisomy 13 protruding tongue ➔ 3 copies in chromosome 13 ➔ Short, broad hands with characteristic palm and fingerprint patterns ➔ Mental, physical, psychomotor retardation ➔ Poor muscle tone ➔ Prone to respiratory disease and heart malformations ➔ Average lifespan of 50 years Figure 11: Karyotype and Symptoms of Patau syndrome Edwards syndrome (47, 18+) Figure 8: Child with Down syndrome ➔ Also known as Trisomy 18 ➔ 3 copies in chromosome 18 Figure 9: Karyotype of Trisomy 21 Figure 12: Karyotype and Symptoms of Edwards syndrome ➔ The ovum is the source of the extra chromosome 21 in about 95% of cases. POLYPLOIDY _______________________________________________________ ➔ The probability of having a child with Down More than two sets of chromosomes syndrome increases with the age of the mother. Figure 10: Incidence of Down syndrome births related to maternal age Figure 13: Polyploidy BIO 130 LEC LU 2 SEM 1 | IMED 2030 Page 3 of 10 SAMSON, SD; AGNES, NC; VITOR, GMZ; REYES, JCDC Chromosomal Disorders & Sex Determination BIO 130 LEC INTARMED 2030 | Prof. Bordallo/Leonardo | LU2 SEM 1 | SY. 2023-2024 Triploidy VARIATION IN CHROMOSOME STRUCTURE ➔ May arise from nondisjunction of all chromosomes at meiosis I, producing a diploid DELETION _______________________________________________________ gamete that is then fertilized by a haploid gamete. There is a missing portion of a chromosome The segment without the centromere is lost in daughter cells after mitosis or meiosis. Terminal Deletion ➔ Deletion occurs towards the end of a chromosome Intercalary Deletion ➔ Deletion occurs from the interior of a chromosome Figure 14: Nondisjunction in Meiosis I ○ Nondisjunction in meiosis I → diploid gamete (2n) → fertilized by a normal haploid gamete (n) → zygote with three copies of each chromosome: triploid (3n) ○ Rarely, two sperm cells can fertilize an egg to form a triploid zygote ○ May cause miscarriage or death within first few days of life. ○ Multiple birth defects: Heart defects Abnormal brain development Adrenal and kidney defects Figure 16: Terminal Deletion and Intercalary Deletion Spinal cord malformations Abnormal facial features Cri du chat syndrome (46, 5p-) Liver and gallbladder defects ➔ Small terminal deletion in short arm (p arm) of Twisted intestines chromosome 5 (Red arrow, Figure 17) Deformities in fingers and toes Tetraploidy ➔ May be produced when sister chromatids in the early embryo separate at anaphase but the cells fail to divide producing four copies of each type of chromosome (4n) Figure 15: Tetraploidy ➔ Very rare in human pregnancies and usually die Figure 17: Karyotype of Cri du chat syndrome during first days or months ➔ Case of a 26-month-old girl with tetraploidy: ○ Abnormal glottis and larynx = cry similar to ◆ Facial dysmorphism meowing of cat ◆ Severely delayed growth ○ Gastrointestinal and heart complications ◆ Developmental delay ○ Mental retardation ○ Usually due to sporadic loss of chromosome segment in gametes, thus, not inherited BIO 130 LEC LU 2 SEM 1 | IMED 2030 Page 4 of 10 SAMSON, SD; AGNES, NC; VITOR, GMZ; REYES, JCDC Chromosomal Disorders & Sex Determination BIO 130 LEC INTARMED 2030 | Prof. Bordallo/Leonardo | LU2 SEM 1 | SY. 2023-2024 DUPLICATION _______________________________________________________ Pericentric inversion There is a repeated segment of a chromosome. ➔ Includes the centromere ➔ A loop is formed ◆ A portion is broken at the point where it overlaps itself ◆ The part reattaches but in an inverted sequence Figure 18: Misalignment of homologous chromosomes Misalignment of homologous chromosomes during meiosis results in unequal crossing over. Gametes formed: Figure 21: One possible origin of a pericentric inversion ○ Normal (chromosome 1 and 4) ○ With deletion (chromosome 2) ○ With duplication (chromosome 3) Not always harmful; has low effect Important in the process of evolution ○ Application in gene/protein families 15q11-q13 duplication syndrome ○ Also known as dup15q syndrome ○ Found in humans ○ Signs and symptoms vary: Poor muscle tone Moderate to severe intellectual disability Figure 22: Pericentric inversion Autism spectrum disorder (ASD) Epilepsy ○ Heterozygous Pericentric Inversion May form abnormal gametes One chromosome is normal while the other is inverted Forms inversion loop to compensate for sequence of genes Reduces fertility of individual ○ Pericentric inversion in chromosome 9 Found in humans Common (~1.6%) Variable effects: No increased reproductive risk Infertility Spontaneous abortion Figure 19: 15q11-q13 duplication syndrome in humans INVERSION _______________________________________________________ A segment of a chromosome is turned 180o within a chromosome Rearrangement of linear sequence No loss or gain of genetic information BIO 130 LEC LU 2 SEM 1 | IMED 2030 Page 5 of 10 SAMSON, SD; AGNES, NC; VITOR, GMZ; REYES, JCDC Chromosomal Disorders & Sex Determination BIO 130 LEC INTARMED 2030 | Prof. Bordallo/Leonardo | LU2 SEM 1 | SY. 2023-2024 TRANSLOCATION _______________________________________________________ Movement of a chromosome segment to a different location in the genome Not the same as crossing over No loss or gain of genetic information Reciprocal Translocation ➔ Exchange of parts between nonhomologous chromosomes Figure 25: Possible origin of a reciprocal translocation between two nonhomologous chromosomes Figure 23: Heterozygous Pericentric Inversion Chronic Myelogenous Leukemia (CML) ○ Reciprocal translocation occurs between Paracentric inversion chromosome 9 and 22 ➔ Does not include the centromere Chromosome 9: C-ABL gene Chromosome 22: BCR gene ○ Heterozygous Paracentric Inversion ○ Forms a Philadelphia chromosome ◆ May form abnormal gametes The BCR-ABL fusion protein stimulates white ◆ Forms dicentric bridge blood cells to proliferate even in the absence of growth signals Figure 26: Formation of the Philadelphia chromosome Robertsonian Translocation ➔ Involves a fusion of the long arms of two nonhomologous acrocentric chromosomes Figure 24: Heterozygous Paracentric Inversion BIO 130 LEC LU 2 SEM 1 | IMED 2030 Page 6 of 10 SAMSON, SD; AGNES, NC; VITOR, GMZ; REYES, JCDC Chromosomal Disorders & Sex Determination BIO 130 LEC INTARMED 2030 | Prof. Bordallo/Leonardo | LU2 SEM 1 | SY. 2023-2024 II. SEX DETERMINATION Female: XX Male: XY Figure 29: Karyotype of a normal human female (left) and a normal human male (right) Primary sex determination ➔ Determination of gonads (ovaries or testes) is by the sex chromosomes Figure 27: Robertsonian Translocation Secondary sex determination ○ Causes familial (inherited) Down syndrome ➔ Determination of the male or female phenotype Robertsonian translocation of chromosomes outside the gonads by hormones produced by 14 and 21 gonads Chromosome number: 46 Figure 30: Sex determination in placental mammals During gametogenesis ○ Pair of chromosomes segregate into gametes so Figure 28: Translocation of Down syndrome that each gamete only contains one chromosome ○ Female gamete (eggs): contains an X chromosome ○ Male gamete (sperm): Half contains a Y chromosome Other half contains X chromosome ○ Sex is determined by type of sperm (if X or Y bearing) fertilizing the egg BIO 130 LEC LU 2 SEM 1 | IMED 2030 Page 7 of 10 SAMSON, SD; AGNES, NC; VITOR, GMZ; REYES, JCDC Chromosomal Disorders & Sex Determination BIO 130 LEC INTARMED 2030 | Prof. Bordallo/Leonardo | LU2 SEM 1 | SY. 2023-2024 SEX DETERMINATION OF DIFFERENT ANIMALS MAMMALIAN PATTERN OF SEX DETERMINATION Figure 31: Sex determination in birds (left) and bees (right) Table 1: Sex determination of different animals MALE FEMALE Mammals XY XX Birds ZZ ZW (homogametic sex) (heterogametic sex) Other insects From unfertilized From fertilized egg (bees, wasps, egg (haploid) (diploid) Figure 32: Development of gonads and their ducts in ants) mammals Drosophila X:0 = 0.5 X:A = 1.0 (fruit fly) - e.g. one X chromosome - e.g. XX and two Early stages of development and 2 sets of autosomes sets of autosomes ○ 4-7 weeks in humans OR ○ Gonads (mesodermal) - sexually indifferent / - XY and 2 sets of autosomes bipotential ○ Have both male (Wolffian ducts) and female (Müllerian ducts) reproductive ducts Table 2: Ratios of X chromosomes to autosomes in different sexual phenotypes in Drosophilia melanogaster By sixth week X- Autosome (A)X:A Sex ○ Germ cells (precursors of sperm or eggs) migrate Chromosomes sets Ratio to gonads and surrounded by mesodermal cells 3 2 1.50 Metafemale MALE DEVELOPMENT (XY EMBRYO) 4 3 1.33 Metafemale Bipotential gonads differentiate into testes 4 4 1.00 Normal female Y chromosome carries Sry gene (sex-determining 3 3 1.00 Normal female region of the Y chromosome) ○ Encodes the testis-determining factor (TDF) 2 2 1.00 Normal female By eighth week: 2 3 0.66 Intersex ○ Mesodermal cells in gonads proliferate and differentiate 1 2 0.50 Normale male ○ One subset differentiates into Sertoli cells Secrete anti-Müllerian hormone (AMH)/ 1 3 0.33 Metamale Müllerian-inhibiting factor (AMF) Destroys Müllerian ducts BIO 130 LEC LU 2 SEM 1 | IMED 2030 Page 8 of 10 SAMSON, SD; AGNES, NC; VITOR, GMZ; REYES, JCDC Chromosomal Disorders & Sex Determination BIO 130 LEC INTARMED 2030 | Prof. Bordallo/Leonardo | LU2 SEM 1 | SY. 2023-2024 Surround incoming germ cells to form testis GENETIC MECHANISMS cord at central region of developing testes Germ cells migrate into periphery of OF PRIMARY SEX DETERMINATION tubules and become spermatogonial cells TRANSCRIPTION FACTORS IN BIPOTENTIAL GONAD _______________________________________________________ ○ One subset differentiate into Leydig cells Secrete testosterone Proteins that regulate the transcription of genes Cause differentiation of Wolffian ducts: Synthesized in the bipotential gonad Epididymis 1. Wt1 Vas deferens 2. Lhx9 Seminal vesicle 3. GATA4 In urogenital sinus, testosterone is converted 4. Sf1 to dihydrotestosterone (DTH) which stimulates formation of: IF Y CHROMOSOME IS ABSENT (XX) Penis Prostate gland TFs increase synthesis of the following proteins in the Scrotum bipotential gonad: 1. Wnt 4 FEMALE DEVELOPMENT (XX EMBRYO) Paracrine factor 2. R-spondin1 (Rspo1) Bipotential gonads differentiate into ovaries Wnt 4 and Rspo1 stimulate Wnt pathway, resulting in Germ cells are surrounded by surface epithelial cells the accumulation of protein β-catenin (transcription ○ Germ cells differentiate into eggs (ova) regulator) ○ Epithelial cells differentiate into granulosa Mesenchyme cells differentiate into thecal cells Actions of β-catenin ○ Further activates transcription of genes for Rspo1 Thecal cells and granulosa cells: and Wnt4 ○ Together, form follicles that enclose germ cells ○ Together with TF Fox12, activates follistatin gene ○ Produce estrogen Follistatin (protein product) helps organize Stimulates differentiation of Müllerian duct: ovary’s granulosa cells Uterus ○ Prevents Sox9 synthesis (testis-determining factor) Oviducts Cervix Upper portion of vagina Wolffian duct degenerates due to insufficient testosterone ANDROGEN INSENSITIVITY SYNDROME XY individuals can have defective receptors for testosterone Figure 33: Schematic diagram of Fox12 deletion Target cells cannot respond to testosterone Fox12 gene expression is increased in ovaries Phenotype ○ Maintains ovarian structure ○ Undescended testes (SRY gene present) ○ Deletion in adult ovaries activates Sox9 gene and ○ Female external sex characteristics, labia and transforms ovary into a testis clitoris Cells respond to estrogen from adrenal glands ○ No uterus and oviduct Müllerian ducts degenerate in response to AMH BIO 130 LEC LU 2 SEM 1 | IMED 2030 Page 9 of 10 SAMSON, SD; AGNES, NC; VITOR, GMZ; REYES, JCDC Chromosomal Disorders & Sex Determination BIO 130 LEC INTARMED 2030 | Prof. Bordallo/Leonardo | LU2 SEM 1 | SY. 2023-2024 Dmrt1 gene maintains testicular structure IF Y CHROMOSOME IS PRESENT (XY) ○ Deletion transforms Sertoli cells into ovarian granulosa cells ○ Overexpression in female ovaries transforms ovarian tissue into Sertoli-like cells IMPORTANCE OF TIMING Sry gene only functions in brief time window If not activated, ovary-forming pathway is activated In mouse embryo, delay in Sry gene activation by 6 hours led to ovary development instead of testes TEMPERATURE-DEPENDENT SEX DETERMINATION Evident in most turtles, all crocodiles and alligators Figure 34: Representation of Y chromosome Expression of genes for male and female differentiation is influenced by temperature TFs activate Sry in bipotential gonad ○ Sry: sex-determining region of Y chromosome; RED-EARED SLIDER TURTLE _______________________________________________________ testis-determining factor; acts as a TF Together with another TF, Sry activates Sox9 gene EGG TEMP INCUBATION SEX (autosomal gene) and other genes that form Sertoli cells Below 28℃ All males Functions of Sox9 protein Above 31℃ All females ○ Activates transcription of genes for testes formation 28℃ - 31 ℃ Males and females Ex. Gene for fibroblast growth factor 9 (Fbg9) - proliferation and differentiation of Sertoli cells; repression of Wnt signaling SNAPPING TURTLE _______________________________________________________ ○ With Sry, blocks ovary-forming pathway by inhibiting β-catenin EGG TEMP INCUBATION SEX ○ Activates transcription of genes for anti-Müllerian hormone [Cool] At or below 22℃ All females ○ Activates own promoter = expressed for longer [Hot] At or above 28℃ Steroidogenic factor 1 (SF1) Intermediate temperature Males ○ Expressed at high levels in the developing testis ○ With Sry, activates Sox9 in Sertoli cells ○ With Sox9, activates gene transcription for anti-Müllerian hormone ○ Activates genes that encode enzymes for testosterone synthesis in Leydig cells Figure 35: Schematic diagram of Dmrt1 gene’s importance BIO 130 LEC LU 2 SEM 1 | IMED 2030 Page 10 of 10 SAMSON, SD; AGNES, NC; VITOR, GMZ; REYES, JCDC