Sex Determination and Sex Chromosomes

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Sex Determination and Sex Chromosomes

• Some species display no evidence of sexual
  reproduction
• Some species alternate between short periods of
  sexual reproduction and long periods of asexual
  reproduction
• Most diploid eukaryotes use sexual reproduction
  as the sole means of producing new members of the
  species

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Sex Chromosomes

• Heteromorphic chromosomes such as X-Y pair often
  called sex chromosomes
• But sex not really determined by chromosomes
• Genes are the underlying basis for sex
  determination
• Some on sex chromosomes, others on autosomes
• Wide range of variation in sex chromosome
  systems, even between closely related species
• Suggests rapid evolution in these instances

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Sexual Differentiation and Life Cycles

• Sexual differentiation
• Primary sexual differentiation
• Involves only the gonads
• Secondary sexual differentiation
• Involves other organs (e.g. mammary glands,
  external genitalia, etc.)
• Individuals may be one sex or possess both sexual
  reproductive systems at the same time
• One sex (unisexual, dioecious and gonochroic)
• Two sexes ( bisexual, monoecious, hermaphroditic)

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Model Organism - Chlamydomonas

• Green algae with infrequent periods of sexual
  reproduction
• Haploid for most of life cycle, mitotic division
• Under unfavorable conditions for specialized
  haploid daughter cells that function as gametes
• Isogametes (both look similar) fuse to form
  diploid zygote (more resistant to conditions)
• Meiosis produces haploid cells when favorable
  conditions return

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Chlamydomonas

• Two mating types (mt and mt-)
• Plus strains only fuse with minus strains and
  vice versa
• Fertilization produces zygote
• Subsequent meiosis produces four zoospores
• Two mt and two mt-
• Although appear similar, differences exist
  (surface structures, etc.)

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Mating Types

• Mating always involves one mt and one mt-
  isogamete

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Zea mays

• Common corn plant
• Dominant form is the diploid (as is the norm with
  seed plants)
• Meiosis and fertilization link haploid/diploid
  phases (fig 7-3)
• Monoecious
• Sex determination occurs differently in different
  tissues (determination occurs during development)
• Stamen/tassels - 4 haploid microspores -
  pollen grains(two nuclei each)
• Pistil - one of four megaspores survives and 3
  mitoses produce 8 nuclei

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Zea mays Fertilization

• Two megaspore nuclei fuse to become endosperm
  nucleus
• 3 nuclei , including oocyte nucleus, remain at
  micropyle (where sperm enters)
• 2 sperm nuclei enter embryo sac
• One fertilizes endosperm (3n)
• One fertilizes oocyte (2n)
• Each double fertilization produces a kernel (up
  to 1000 per ear)

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Zea Mays Life Cycle
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Caenorhabditis elegans

• C. elegans nematode worm
• 959 cells total, each with known lineage tracing
  back to original zygote
• Two sexual phenotypes
• Males (1 of hermaphrodite self-cross progeny)
  and hermaphrodites (99 of hermaphrodite
  self-cross)
• Hermaphrodites are X,X, males X,O (one X only)
• Sex determined by gene dosage (X to autosomes)

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C. elegans
XX
XO
XX
XO
XX
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X and Y Chromosomes

• Early observations by Henking and McClung
• 1906 Edmund Wilson observes that female Protenor
  (insect) have 14 chromosomes, males have 13
• Gametes from females have 7, from males 6 or 7
• Fertilization yields zygotes with 13 (male) or 14
  (female) chromosomes
• XX/XO mode of sex determination

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XX, XO
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X and Y Chromosomes

• Wilson continues
• Insect Lygaeus turicus
• Both sexes have 14 chromosomes
• Females have 2 X chromosomes, males have one X
  and a smaller heterochromosome named Y
• Females produce 6A X gametes, males produce 6A
  X and 6A Y gametes
• Male of species is heterogametic
• Female is homogametic
• Female is heterogametic in some XX/XO and XX/XY
  species (ZZ/ZW is often used in these cases)

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XX, XY
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Human Y Chromosome

• Early 1900s human females thought to have extra
  chromosome (if male 46, then female 47)
• 1920s Theophilus Painter observed small Y
  chromosome (but total number was 45-48)
• 1956 human chromosome number set at 46 by Tjio
  and Levan
• Improved staining/banding techniques
• 22 pair autosomes, 1 pair sex chromosomes
• But does Y determine maleness, or the absence of
  2 X chromosomes (presence of one).?

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Human Karyotype
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Klinefelter Syndrome

• Noted about 1940
• Aberrant sexual development (feminized male)
• Generally have genitalia and ducts but
  rudimentary testes and produce no sperm
• Intelligence often lower than normal/average
• Karyotype
• 47 chromosomes
• XXY (designated 47,XXY), have a Barr body (but
  can have 3 or 4 X chromosomes or 3X2Y karyotypes)
• Product of nondisjunction during gametogenesis
• 2 of 1000 male births

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Klinefelter Karyotype
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Turner Syndrome

• Female external genitalia and internal ducts
• Rudimentary ovaries
• Often normal intelligence
• Karyotype
• 45 chromosomes
• XO (designated 45,X)
• Product of nondisjunction during gametogenesis
• 1 per 2000 female births

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Turner Syndrome Karyotype

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Bottom Line

• Maleness in humans is determined by the presence
  of an X chromosome
• 2 X chromosomes also give one a Barr body but XXY
  is still male
• The absence of a second X chromosome doesnt make
  one a male (the Y chromosome is not a space
  holder with nothing to do with sex
  determination)
• Human females are females because they dont have
  a Y chromosome (default sex?)

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47,XXX

• Occurs about 1/1200 female births
• Variable phenotypic expression from perfectly
  normal to sterile, underdeveloped secondary sex
  characteristics and some MR
• Two Barr bodies
• 48,XXXX and 49,XXXXX also occur (rarely)
• Similar but more pronounced symptoms
• Only one X chromosome not in Barr body form

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47, XYY Condition

• 1965, Patricia Jacobs
• 9 of 315 males in Scottish prison had karyotype
• Significantly above average for normal
  population
• Correlation between karyotype and criminal
  behavior?
• All above normal height and suffered personality
  disorders, 7 of 9 subnormal intelligence
• Summary of further studies in Table 7.1

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• About 1/20 tall criminally insane males were XYY
• Nearly 50 times the control group average
• But many normal XYY males present in population

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XYY Follow-up

• Study by Harvard investigators Walzer and Gerald
• Identified new 47,XXY babies to follow their
  behavior pattern development
• Federal funded project
• Project dropped by investigators due to public
  pressure (study still supported by granting
  agency and fellow faculty)
• Self-fulfilling prophecy.????
• Now correlation between karyotype and phenotype
  perhaps not as clear?

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Y Chromosome and Male Development

• Human Y chromosome smaller with far fewer genes
  than X chromosome
• But does have many more genes after completion of
  human genome project (once thought a genetic
  wasteland)
• Y chromosome has 2 small regions homologous to
  portions of X chromosome (5 of Y)
• At termini of Y chromosome, pseudoautosomal
  regions (PARs)
• Allows homologous pairing and recombination
  during meiosis/gametogenesis
• Remaining 95 called MSY (male-specific region of
  the Y)
• About half/half euchromatin with genes and
  heterochromatin without

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MSY and SRY

• SRY
• Sex-determining region of Y chromosome
• In euchromatin of MSY adjacent to PAR
• Encodes gene not found on X chromosome
• Gene product is called testis-determining factor
  (TDF)
• Conserved in all mammals studied to date
• XX males found with only SRY region translocated
  to another chromosome, and
• XY females found with SRY gene missing from Y
  chromosomeSRY product starts the cascade
• Verified by introducing Sry into transgenic XX
  mice

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Human Y Chromosome
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MSY Region

• About 23 million bp in size
• 15 is the X-transposed region with 99 homology
  to X chromosome region Xq21 and encodes 2 genes
• 20 is X-degenerative region which has much less
  homology (but related) to X, encodes 14
  functional genes (including SRY plus many genes
  expressed ubiquitously) and 13 pseudogenes
• 30 is the ampliconic region with 60
  transcription units with no X chromosome
  homologs, and include gene families with up to
  98 sequence identity
• Include many genes related to testes
  development/function and mutations in these genes
  responsible for much male infertility observed in
  humans

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Human Sex Ratios

• Primary sex ratio
• Male to female ratio at conception
• Secondary sex ratio
• Male to female ratio at birth
• Human secondary sex ratios vary from 1.025
  (African-American) to 1.06 (U.S. Caucasian) to
  1.15 (Korean)
• 1948 data suggested U.S. Caucasian primary sex
  ratio 1.079, but now believed to be 1.20-1.60

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Human Sex Ratios

• Assumptions
• Males produce equal numbers of X- and Y-bearing
  sperm
• Each type of sperm has equal viability and
  motility in female reproductive tract
• Egg surface equally receptive to both types of
  sperm
• Could the smaller Y chromosome make those sperm
  lighter and therefore faster?
• Is increase in male zygote numbers necessary to
  compensate for losses due to increased expression
  of X-linked deleterious alleles?

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Dosage Compensation

• Gene dosage very important in mammalian species
  (not so true for plants)
• Correct number of chromosomes
• Correct ratio of chromosomes/genes
• Most abnormal karyotypes involving autosomes
  lethal at early stage of development
• How can sex chromosome variation (XX vs. XY) be
  toleratedintended?
• Dosage compensation

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Barr Bodies

• Darkly staining region found in nuclei of normal
  females (46,XX) and not in normal males (46,XY)
• Also called sex chromatin body
• XXY males have one, XXX females have two, others
  more
• Why are individuals with abnormal karyotypes
  involving sex chromosomes generally completely
  normal?
• Perhaps inactivation isnt complete
• Perhaps damage is done developmentally before
  inactivation occurs

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Barr Bodies

• Female cells shown to right at top, male cell to
  right at bottom

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Karyotypes and Barr Bodies
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Lyon Hypothesis

• 1961, Mary Lyon and Liane Russel, independently
• Inactivation of X chromosome is random (which
  one), occurs in somatic cells at an early stage
  of embryonic development and is then passed on to
  progeny cells by mitosis
• Female mice and coat color genes, calico cats and
  fur color/patterns
• Also human G6PD (glucose 6-phosphate
  dehydrogenase
• No fibroblast clone expresses more than one
  isozyme

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Calico Cats

• Orange and black patches reflect X chromosome
  inactivation, white patches due to another gene

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Mechanism of Inactivation

• X-chromosome encoded X-inactivation center (Xic)
  is major control unit
• About 1 million bp in size
• Four genes, one encodes Xist (X-inactive specific
  transcript)
• No ORF on transcript
• Structural RNA, acting in mechanism of
  inactivation
• Expression of Xic leads to inactivation of
  chromosome expressing the Xist locus (cis-acting)
• All X chromosomes express at low level, one at
  high and is inactivated
• Deletion of region makes chromosome unable to be
  inactivated

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Unanswered Questions
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Sex Determination in Drosophila,or Y isnt
always the answer

• Drosophila are XX and XY like humans
• But Calvin Bridges in 1916 showed the Y
  chromosome is not involved in sex determination
• Studied female flies resulting from
  nondisjunction
• XXY, XO, XX, XY and various sex chromosome
  combinations with 3N autosomes

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Drosophila Karyotypes and Sex
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Drosophila Genes

• Sxl, tra, dsx and others involved
• tra activated by Sxl which influences expression
  of dsx
• dsx product activates either male- or
  female-specific genes
• Depends upon how dsx RNA transcript is spliced
• Alternative splicing cascade involved

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Dosage Compensation in Drosophila

• No Barr body formed in XX flies
• Sxl gene is active in females and turns off
  autosomal genes that would increase expression of
  X-linked genes
• Sxl gene does not turn off the genes in XY males,
  allowing them to turn up expression of X-linked
  genes, providing a similar level of overall
  expression as found in XX females

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Reptile Sex Determination

• Temperature-dependent sex determination or TSD
• In contrast to chromosomal or genotypic sex
  determination (CSD and GSD)
• Many reptile species do use ZZ/ZW or XX/XY
• Three patterns of TSD involving temperature of
  incubation of the eggs

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Temperature-Dependent Sex Determination