Chromosome Theory of Inheritance 1902 Sutton and Boveri

A chromosome is a linkage group of Mendelian factors (GENES)

How many linkage groups in the human species?

1920s Morgan et al. Genes are in a linear sequence on the

chromosomes, they can be mapped

Chromosomes in most animals pairs of autosomes 1 pair sex chromosomes

XY heterogametic XX homogametic

Human karyotype ->

Do more chromosomes mean more intelligence?

Human 46Chimpanzee 48Dog 78Cat 72Alligator 32Goldfish 94Mosquito 6Potato 48Baker’s yeast 34

I. Mammalian sex determination = the Y system

A. Embryo is neither male nor female

Week 7 How does embryo “knowto become male?

XY embryo sex chromosomes The Y determines sex…. XY = male XX =

female

B. SRY gene encodes TDF (Testes determining factor, 1990)

SRY (sex determining region Y) Short arm (p) TDF is a 20 aa protein (a

transcription factor) TDF stimulates the growth of

testes --> testosterone ---> sperm ducts,

male brain “sensitization”

XX males: If SRY crosses over to the X chromosome during meiosis (formation of sperm)

Father during meiosis

X from father + X from mother

A 17 year old female presented with “streak” ovaries, no uterus, no menstrual cycle

XY female Embryo has Y chromosome but does not

develop as male Mutation in SRY ?

II. Other sex determination systems

A. Drosophila

Ratio of X to sets of autosomes embryo “calculates” ratio

X/A = 1 or >1 ------> female

X/A = 0.5 or <0.5 --------> male

X/A between 0.5 and 1 ---> intersex

What is the sex of an XY fly with 2 sets of autosomes? What is the sex of a fly with with 2 sets of autosomes

but 1 X chromosome What is the sex of a triploid fly with 2 X chromosomes?

B. ZW system - birds Females are ZW

(heterogametic) Males are ZZ

(homogametic)

PCR analysis of sex chromosomes

C.Temperature sex determination (TSD) In some reptiles sex is not

determined genetically! (Varies widely)

majority of endangered reptiles use TSD - sea turtles, Galapagos tortoises, alligators, crocodiles

Parthenogenesis – eggs

develop without sperm

(asexual)Komodo dragonParthenogenesisZW system, all offspringof parthenogenesis are maleWhy?

IV. Dosage Compensation (mammals) Females have 2 Xs, males have 1 X. Do

females have an extra dose of X-linked genes/alleles?

X chromosome inactivation Lyon, 1961

Observe dense “Barr body” at edge of nucleus

in female cells Heterochromatic (stains darker)

Male cell female cell cell with 2 Barr bodies

Number of X chromosomes?

Random X-inactivation, mechanism

~1000 cell embryo random inactivation of X

XIC, Xist gene on X chromosome transcribed 24 hours prior to inactivation mRNA “cages” X-chromosome caged X becomes a Barr body

XICX

X

Which X is inactivated appears to be random

mRNA

Embryo develops patches

Barr body

Female mosaics All females heterozygous for X-linked traits

are mosaics for those traits.

red/green colorblindness XCXc

phenotype = ?

Look at retina of heterozygous female

Anhydrotic ectodermal dysplasiaXAXa females XaY malesTooth + nail

abnormalities, life

threatening hyperthermia,

sparse hair

Similarities and differences X and Y Most genes on Y are for

development and fertility (Human has ~80 Y genes) (Kangaroo has only SRY on the Y)

~ 80 genes

Pseudoautosomal region of the X and Y

•~12 genes on X and Y•regions allow X and Y to pair during meiosis

•pseudoautosomal genes are also transcribed from the inactivated X! •both males and females have 2 active copies of these genes

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Chromosomal AbnormalitiesKARYOTYPE

1. Obtain white blood cells from or fetal cells from amniotic fluid

2. Proliferation via growth factor add colchicine at metaphase to arrest spindle formation

3. add water to swell cell -> squash

4. stain ->photograph

Detects number of chromosomes,

sex, chromosomal abnormalities

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Amniocentesis usually done week 14

Karyotype and analyze fluid for enzymedefects

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Chorionic villus sample (CVS) usually done week 8

More risk, butearlier results

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Arrange in pairs according to: decreasing size

centromere position

banding pattern

ACROCENTRIC

METACENTRIC

SUBMETACENTRIC

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metacentric (1) submetacentric (9)

p arm is the upper, shorter arm

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Normalmale

46, XY

Which are meta-, submeta-acrocentric?

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Aneuploidy (versus euploidy) Trisomy (not triploid)

47, 21+

(1/800 live births)

21 may be small, but contains 33,546,361 bp of DNA!

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Down Syndrome (J. Langdon H. Down, 1866)

effects Developmental delays Possible heart defects,

hearing loss, hypotonia, thyroid problems, obesity

Epicanthic eye folds Wide tongues Greater risk of

Alzheimer’s

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Trisomy 13 (Patau) Fatal< 1 year (usually) Deaf, blind, clyclopia, polydactly,

cleft palate 1/5000 live births

47, XY, 13+

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47, XY, 18+ (Edward’s) < few months

1/5000 live births

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Human trisomies of the sex chromosomes (see pg 293) 47, XXY = Klinefelter’s 47, XXX 47, XYY

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Monosomy (only 1 viable in humans!) 45 X,

Turner Syndrome (1/2000 live births)

Partial monosomy 46, 5p- Cri du Chat Arises due to a deletion on the short arm of

chromosome 5

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Cri du Chat 46, 5p- 1/50,000 live births

pseudodominance for deleted region

Microcephaly, myotonia, “cry of cat”, retardation

if individuals make it past childhood, symptoms lessen

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Polyploidy = extra SETS of chromosomes # in humans Triploid, tetraploid Octoploid etc..

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Many plants are polyploid

Some bees and wasps are monoploid

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In humans

Monosomy

Trisomy

Tetrasomy

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can observe large ones by karyotype If centromere is lost, then chromosome will be lost Heat, chemicals, radiation Unequal crossing over during meiosis

Deletions (del)

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46,XX,del(7)(q21.12,q21.2)

Leads to problems during meiosis

Pseudodominance Lethal if both chromosomes

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Duplications segment of a chromosome doubles May be tandem or reverse problems during meiosis

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dup(5)(qter->q33.1::p15.3->qter) Sample of cord blood from

stillborn male with anencephaly

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Inversions (inv) 180o turnaround of segment

no loss of genetic material may change length ratio of p/q arms

Position effect change in gene position with respect to

centromere being near heterochromatic region may

influence expression

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Translocations - segment moves to other chromosome - interstitial or reciprocal exchange

t (13;14) Individual has all

genetic material, but what about gametes?

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t(11;13) (q21;q14.3)

the parent who has the translocation is phenotypically normal as all genetic info is present

The gametes, however, are not as evidence by multiple miscarriages

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Translocation (cont.) Robertsonian fusion

ends of 2 acro- or telocentric break/fuse 45 chromosomes but no, or little, loss of genetic

material