Sex Chromosomes and chromosome mutatons

Meiotic nondisjunction

-Chromosomes don’t split

Monosomies

-missing chromosomes

trisomies

-extra chromosomes

Klinefelter Syndrome

-47, XXY

-has an extra X

-Tall stature, slightly feminized physique, osteoporosis, small testies, long arms and legs

Turner Syndrome

-45, X

-Only monosomy that is viable

-Short stature, low hairline, elbow deformity, no menstruations, etc

Trisomy X

-47, XXX

-Occurs in about 1/1000 live females birth

-Occasionally affected individuals have learning disabilities but no major physical anomalies, basically normal

-Associated with menstrual irregularities or infertility, most are diagnosed in fertility clinicals

-With increasing number of XX chromosomes, phenotype is more severe (mental and physical abnormalities)

47, XYY syndrome

-Occurs in about 1/1000 live male births

-Men are very tall and have lower IQ but few physical problems

-Increased incidence of minor behavioral disorder

Y chromosome contains _____ genes than the X chromosome

-fewer

-Y chromosome has at least 75 genes, X chromosome has 900-1400 genes

Pseudoautosomal regions (PARS)

-at both ends of the Y chromosome share homology with regions on the X chromosome

-They synapse and recombine during meiosis

-Critical to segregation of the X and Y chromosomes during male gametogenesis

Male-specific region of the Y (MSY)

Non-recombination region makes up 95% of the Y chromosome

Euchromatin

DNA is open and expressed

Heterochromatin

DNA is tightly wound, not expressed

Sex-determining region Y (SRY) gene

-encodes the testis-determining factor (TDF) and is highly conserved among mammals

Testis-determining factor (TDF)

-is a protein that causes the non-differentiated gonadal tissue of the embryo to form testes

-If SRY has translocated to another chromosome in an XX individual, they will develop into a male

-Individuals who are XY, but are missing SRY develop into females

-TDF is likely a transcription factor that directly interacts with the regulatory sequences of other genes that determine sexual differentiation

Primary sex ratio

-reflects the proportion of males:females conceived in a population

-1.2-1.6 is the current estimation for the US caucasians

-Many more males than females conceived

-Y-bearing sperm may be more motile than X-bearing sperm because the Y chromosome is smaller

Secondary sex ratio

-reflects the proportion of males:females born in a population

-Male embryos have higher fetal mortality, more likely to die during development

Dosage compensation

-a genetic mechanisms that balances the dose of X chromosomes in males and females

-Males only have one X while females have 2, but males and females have similar expression pattern for genes on the X chromosome

-Females have 1 inactive X chromosome in each cell

X chromosome inactivation

-occurs during embryogenesis

-X chromosome remains active or inactive in future mitosis

-Inactive X chromosome appears as a Barr body

-X inactivation reverses in the female germline so all oocytes contain active X chromosomes

Lyon’s Hypothesis

-stating that only one of the two X-chromosomes in a female is functional, the other having become inactive early in development

-Either the maternal or the paternal X-chromosome may be inactivated in any given cell

-Mosaic patterns of black and yellow-orange patches in female calico and tortoiseshell cats are due to random X inactivation

-Genes for coat color are on the X chromosome, Males are hemizygous and have only 1 allele for coat color

X-inactivation center (Xic)

-involved in inactivation of X chromosome

-is expressed only on the inactive X chromosome, contains 4 genes, including the X-inactive specific transcript (XIST) gene, which is critical to inactivation, mRNA transcribed from XIST coats the inactive X, causing transcription silencing

-Inactivation of X chromosome occurs very early in embryogenesis

-Inactive X is maintained as a Barr body during future cell divisions

Euploidy

-refers to having 1 or 2 sets of haploid chromosomes

-Haploid gametes and diploid somatic cells are euploid

-Complete haploid sets are present

Polyploidy

-refers to having more than 2 sets of haploid chromosomes (Ex: triploid)

Only viable human trisomies are: (PED)

-Trisomy 13→ Patau syndrome

-Trisomy 18→ Edward syndrome

-Trisomy 21→ Down syndrome

-Only trisomy 21 can survive into adulthood

Patau syndrome

-Trisomy 13

-Mental and physical deficiencies, wide variety of defects in organs, large triangular nose, early death

Edward syndrome

-Trisomy 18

-Mental and physical deficiencies, facial abnormalities, extreme muscle tone, early death

Down Syndrome

-Trisomy 21

-Mental deficiencies, abnormal pattern of palm creases, slanted eyes, flattened face, short stature

-75% are due to nondisjunction in meiosis I, 95% are maternal in origin, recurrence risk is extremely low

-Incidence increases with maternal age

20-30% of all conceptions among humans are aborted spontaneously

-many of these have chromosome abnormalities

-trisomies for all chromosomes have been observed

most monosomies are 45,X, very few autosomal monosomies

-normal embryonic development requires 23 maternal and 23 paternal chromosomes

Variation and chromosome composition and arrangement

-are due to chromosome breaks

-Chromosomal breaks can spontaneously rejoin

-Sticky ends can alter chromosome structure

-genotype loss, cause a phenotype change

Deletions

-results in chromosomal loss

-Terminal deletions occur at chromosomal ends

-Intercalary (interstitial) deletions occur internally

-Portions with the centromere are usually maintained when the cell divides

-those without centromeres are usually lost during subsequent divisions

-creates imbalance in gene dosage

-microdeletions are sub-microscopic deletions that are often associated with abnormal phenotypes that can manifest as syndromes

-Compensation loops can appear during synapsis and compensates for loss of alleles

Cri-du-chat syndrome

-caused by a deletion in chromosome 5p (46,5p-)

-associated with cognitive impairment, unique facial anomalies, catlike cry in infancy, GI and cardiac complications

-severity of phenotype depends on the size of the deletion, which occurs sporadically in gametes

Duplications

-tend to be less harmful than deletions

-often caused by unequal crossing over (recombination)

-in this situation, it results in a duplication and a deletion, but no gain or loss of genetic material

-also caused by DNA replication errors prior to meiosis

-depends on location for severity

-Genome contains many repetitive sequences that can misalign during synapsis

Charcot-Marie Tooth disease

-caused by a duplication of PMP22 on chromosome 17

-1/2,500 individuals are affected; leads to progressive atrophy of limb muscles

-PMP22 encodes component of peripheral myelin

-overproduction of protein prevents normal processing

-leads to reduced functional protein that impairs myelin formation and slows nerve conduction

-causes muscle weakness, claw toes, reduced function

Gene amplification

-can be a normal phenomenon

-multiple copies of genes encoding ribosomal RNA (rRNA) in metabolically active cells to support protein synthesis, called rDNA

-rRNA is synthesized in the nucleolus→ are formed around loci called nucleolar organizing regions on chr. 13,14, 21, 22

Copy number variants (CNVs)

-are found throughout the genome

-comprise about 12% of the human genome

-are regions at least 1000 base pair in length with 90% sequence identity

-Some CNVs have no phenotypic consequences

-others have been associated with disease (autism, schizophrenia)

-higher CNVs of CCL31 slows the progression of AIDS in HIV positive individuals

-can be caused by unequal recombination or errors in DNA replication

Inversions

-requires 2 breakpoints and rearrange genetic sequences

-No gain or loss of genetic material

-Phenotypic effect depends where the breaks occur

Transactions

-involve exchanges between non-homologous chromosomes

-can occur if sticky ends are recognized by DNA repair enzymes, which attempt to reattach them

-if 2 chromosomal breaks occur simultaneously a translocation can occur

-Reciprocal or balanced translocations result in no gain or loss of genetic material

Robertsonian translocation

-involves acrocentric chromosomes 13, 14, 15, 21, and 22

-pair during meiosis and different chromosome combinations occur in genes

-gametes fertilized from a normal parent will lead to down syndrome in 15% of maternal translocation carriers and 2% of paternal translocation carriers

-Can have a balanced translocation

Fragile X syndrome

-most common form of inherited mental retardation

-X-linked dominant trait with incomplete penetrance

-distinct facial appearance, large ears, long, face, hypermobile joints, macro-orchidism

-caused by an expanded CGG repeat in an untranslated region of the FMR-1 gene

Anticipation

occurs in transmitting females but not males with a premutation and risk increases with number of repeats, increased number by generation

Cross over

a cellular process that happens during meiosis when chromosomes of the same type are lined up. When two chromosomes — one from the mother and one from the father — line up, parts of the chromosome can be switched.