LECTURE PRESENTATIONS

For CAMPBELL BIOLOGY, NINTH EDITION Jane B. Reece, Lisa A. Urry, Michael L. Cain, Steven A. Wasserman, Peter V. Minorsky, Robert B. Jackson

Chapter 15 The Chromosomal Basis of Inheritance

Lectures by Erin Barley Kathleen Fitzpatrick

© 2011 Pearson Education, Inc.

Mendelian inheritance has its physical basis in the behavior of chromosomes

• • • Mendel’s “hereditary factors” were genes today we can show that genes are located on chromosomes the chromosome theory of inheritance states: – Mendelian genes have specific loci (positions) on chromosomes – chromosomes undergo segregation and independent assortment

F 1 Generation LAW OF SEGREGATION The two alleles for each gene separate during gamete formation.

1

R Y r y R Y y r R r Y y

Meiosis All F 1 plants produce yellow-round seeds (

YyRr

).

Metaphase I

R r Y y Y r R y r

LAW OF INDEPENDENT ASSORTMENT Alleles of genes on nonhomologous chromosomes assort independently during gamete formation.

1

R

Anaphase I

Y y

2

R r y

Metaphase II

Y r R y

2

Y

•

Gametes

Y R

1 / 4

YR R Y r y

1 / 4

yr y r r Y

1 / 4

Yr r Y R y

1 / 4

yR R y

the behavior of chromosomes during meiosis accounts for Mendel’s laws of segregation and independent assortment LAW OF SEGREGATION LAW OF INDEPENDENT ASSORTMENT F 2 Generation An F 1



F 1 cross-fertilization 3 Fertilization recombines the

R

and

r

alleles at random.

9 : 3 : 3 : 1 3 Fertilization results in the 9:3:3:1 phenotypic ratio in the F 2 generation.

Morgan’s Experimental Evidence: Scientific

Inquiry

• • • • the first solid evidence associating a specific gene with a specific chromosome came from Thomas Hunt Morgan - an embryologist Morgan’s experiments with fruit flies (Drosophila melanogaster) provided convincing evidence that chromosomes are the location of Mendel’s heritable factors several characteristics make fruit flies a convenient organism for genetic studies – they produce many offspring – a generation can be bred every two weeks – they have only four pairs of chromosomes Morgan recorded wild type (or normal) phenotypes that were common in the fly populations – traits alternative to the wild type are called mutant

phenotypes

Drosophila mutations -

-white eyes (ABC gene mutation) wingless (Wnt mutation) curly winged, short winged (vestigial) forked bristles ebony color, yellow color

Correlating Behavior of a Gene’s Alleles with Behavior of a Chromosome Pair

• • • in one experiment, Morgan mated male flies with white eyes (mutant) with female flies with red eyes (wild type) – the F 1 generation all had red eyes – the F 2 generation showed the 3:1 red:white eye ratio – but only males had white eyes Morgan determined that the white-eyed mutant allele must be located on the X chromosome Morgan’s finding supported the chromosome theory of inheritance

• • Morgan determined that the white-eyed mutant allele must be located on the X chromosome Morgan’s finding supported the

chromosome theory of inheritance EXPERIMENT P Generation F 1 Generation RESULTS F 2 Generation CONCLUSION P Generation X X

w



w



F 1 Generation Eggs

w



F 2 Generation Eggs

w



w w w



w w



w



w



w w



All offspring had red eyes.

X Y

w w



Sperm

w



w

Sperm

• • • • • •

The Chromosomal Basis of Sex

in many organisms there is a chromosomal basis of sex determination XX/XY determination – humans and most mammals and some insects – humans – Y determines the male – fruit flies – 2 X’s determine the female XX/XO determination – some rodents – females = XX – males = XO (absence of a second sex chromosome) ZW determination – birds, some reptiles and some insects – ZW = female • W chromosome possesses sex determining genes – ZZ = male UV determination – some plants and algae – U = female gametophytes – V = male gametophytes haplo-diploid system – bees and ants – diploid = female and sterile males – haplo = males (from unfertilized eggs) – so the queen and control gender

(a) The X-Y system 22



X or 22



Y Sperm (b) The X-0 system (c) The Z-W system 44



XY 44



XX Zygotes (offspring) 22



XX 76



ZW 32 (Diploid) Parents or 22



X 76



ZZ 44



XX 22



X Egg 44



XY 16 (Haploid) (d) The haplo-diploid system

• • •

The Chromosomal Basis of Sex

in humans and other mammals



determination XX/XY

– a larger X chromosome and a smaller Y chromosome for males one X chromosome is inactivated in females the Y chromosome – significantly lower numbers of genes vs. X chromosome (1846 vs. 454) – most of them are responsible for sex determination and development of male reproductive structures – the SRY gene on the Y chromosome codes for a protein that directs the development of male anatomical features • BUT the ends of the Y chromosome have regions that are homologous with corresponding regions of the X chromosome = pseudoautosomal regions

The Chromosomal Basis of Sex

• • • • a gene that is located on either sex chromosome is called a sex-linked gene genes on the Y chromosome are called Y-linked

genes

genes on the X chromosome are called X-linked

genes

X chromosomes have genes for many characters unrelated to sex – whereas the Y chromosome mainly encodes genes related to sex determination – e.g. SRY gene

X-linked Genes

• • • X-linked genes follow specific patterns of inheritance for a recessive X-linked trait to be expressed – a female needs two copies of the allele (homozygous) – a male needs only one copy of the allele (hemizygous) X-linked recessive disorders are much more common in males than in females

X

N

X

N

X

n

Y X

N

X

n

X

N

Y X

N

X

n

X

n

Y Eggs Sperm X

N

X

n

Y X

N

X

n

X

N

Y X

N

X

N

X

n

X

N

Y (a) Sperm X

N

Y Eggs X

N

X

N

X

N

X

N

Y X

n

X

N

X

n

X

n

Y (b) Eggs Sperm X

n

X

N

Y X

N

X

n

X

N

Y X

n

X

n

X

n

X

n

Y (c)

• Some disorders caused by recessive alleles on the X chromosome in humans – Color blindness (mostly X-linked) – Duchenne muscular dystrophy – Hemophilia A and B

• • • •

X Inactivation in Female Mammals

the coloration of a calico cat is the physical manifestation of a phenomenon called X-

inactivation

X-inactivation or lyonization process in mammalian females where one of the two X chromosomes in each cell is randomly inactivated – in marsupials – always the paternally derived X prevents the female from having twice as many X chromosome gene products as a male = dosage compensation the inactive X condenses into a Barr body

Early embryo: Two cell populations in adult cat: Active X Black fur X chromosomes Allele for orange fur Cell division and X chromosome inactivation Inactive X Allele for black fur Orange fur Active X

• • • •

X Inactivation in Female Mammals

X inactivation begins at embryonic development – occurs in the inner cell mass of the blastocyst once a specific X chromosome is inactivated – that one will remain inactive throughout its lifetime – will also be inactivated in all cellular progeny

inactivation is an epigenetic change

– high methylation of DNA and low acetylation of histones – methylation results in the packaging of the X chromosome into heterochromatin – DNA is now a transcriptionally inactive structure reversed in female germ cells undergoing meiosis

Early embryo: Two cell populations in adult cat: Active X Black fur X chromosomes Allele for orange fur Cell division and X chromosome inactivation Inactive X Allele for black fur Orange fur Active X

• • • •

X Inactivation in Female Mammals

active X chromosome is called Xa inactive one is designated Xi if multiple X chromosomes are present (i.e. 3 vs. 2) – only one X chromosome is still Xa – default state is the inactive form hypothesis: autosomally-encoded blocking factor binds to the Xa chromosome and prevents its inactivation – sequence known as the XIC – X inactivation center – may bind these binding factors and prevent inactivation??

• • the XIC of the the Xi chromosome produces a non-coding RNA called Xist RNA – coats the Xi chromosome  inactivation despite the fact that the X chromosome is inactivated – there are genes on Xi that ESCAPE inactivation – these genes are also found on the Y chromosome of males – so there is dosage compensation

Mosaicism

• • • • Mosaicism – two or more populations of cells with different genotypes within a single organism most common forms rise from errors in the first few mitotic divisions of a fertilized zygote – mitotic crossing over!

– Source of genetic variation in asexually reproducing organisms – Can occur in sexually reproducing organisms – Takes place during interphase (G1) other mosaicisms – result from non-disjunction during meiosis and produce trisomies

true mosaicism should NOT be confused with X-inactivation!!!

– all the cells in this cat have the same genotype BUT a different X is

active in different cells

Linked genes tend to be inherited together because they are located near each other on the same chromosome

• • each chromosome has hundreds or thousands of genes (except the Y chromosome) genes located on the same chromosome that tend to be inherited together are called linked genes

How Linkage Affects Inheritance

• • • • Morgan did other experiments with fruit flies to see how linkage affects inheritance of two characters Morgan crossed flies that differed in traits of body color and wing size found a higher percentage of parental phenotypes in the offspring concluded that these genes do not assort independently – body color and wing size are inherited together – reasoned that they were on the same chromosome

P Generation (homozygous) Wild type (gray body, normal wings)

b



b



vg



vg



Double mutant (black body, vestigial wings)

b b vg vg

How Linkage Affects Inheritance

• • • • • Mated true-breeding wild type flies with gray bodies and normal wings (b+b+vg+vg+) with mutants with black bodies and short, vestigial wings

P Generation (homozygous) Wild type (gray body, normal wings)

b



b



vg



vg



F 1 dihybrid (wild type) TESTCROSS

all F1 offspring looked like parents and were heterozygotes performed a test-cross of female F1 with true-breeding male mutants (bbvgvg) – expected a 1:1:1:1 ratio of dominant to recessive

b



b vg



vg

Testcross offspring Eggs

b



vg



b vg b vg

Wild type (gray-normal) Black Sperm

b



vg b vg



Gray vestigial Black normal most offspring looked like the parents PREDICTED RATIOS

only possible if the b and vg genes are linked and did not sort independently during meiosis

If genes are located on different chromosomes: If genes are located on the same chromosome and parental alleles are always inherited together:

b



b vg



vg b b vg vg b



b vg vg b b vg



vg

RESULTS 1 1 965 : : : 1 1 944 : : : 1 0 206 : : : 1 0 185 Double mutant (black body, vestigial wings)

b b vg vg

Double mutant

b b vg vg

F 1 dihybrid female and homozygous recessive male in testcross Most offspring

b

+

vg

+

b vg b

+

vg

+

b vg

or

b vg b vg b vg b vg

• however, nonparental phenotypes were also produced – so body color and wing size are not always linked genetically and can be recombined as a result of crossing over or

genetic recombination

Recombination of Unlinked Genes: Independent Assortment of Chromosomes

• • • offspring with a phenotype matching one of the parental phenotypes = parental types offspring with nonparental phenotypes (new combinations of traits) = recombinant types, or recombinants a 50% frequency of recombination is observed for any two genes on

different chromosomes Gametes from yellow-round dihybrid parent (

YyRr

)

YR yr Yr yR

Gametes from green wrinkled homozygous recessive parent (

yyrr

)

yr YyRr yyrr

Parental type offspring

Yyrr yyRr

Recombinant offspring

• •

Recombination of

parents

Linked Genes: Crossing Over

Gray body, normal wings (F 1 dihybrid) Black body, vestigial wings (double mutant)

b



vg



b vg

Replication of chromosomes

b vg b



vg

 MEIOSIS I: crossing over between the homologous chromosomes of the female parent produces new combinations of alleles (b+ vg and b vg+) MEIOSIS II: some of the eggs are parental and some are recombinants

Meiosis I Meiosis II

b



vg



b vg b vg b



vg



b



vg b vg



b vg

Recombinant chromosomes

b vg

Replication of chromosomes

b vg

Meiosis I and II

b vg b vg b vg

Eggs

b



vg



b vg b



vg b vg



b vg

Sperm

Eggs

b



vg



b vg

Recombinant chromosomes

b



vg b vg



Testcross offspring 965 Wild type (gray-normal)

b



vg



944 Black vestigial

b vg b vg b vg

206 Gray vestigial

b



vg b vg

185 Black normal

b vg



b vg

Parental-type offspring Recombinant offspring Recombination frequency



391 recombinants 2,300 total offspring



100



17%

b vg

Sperm

New Combinations of Alleles: Variation for Normal Selection

• • • recombinant chromosomes bring alleles together in new combinations in gametes random fertilization increases even further the number of variant combinations that can be produced this abundance of genetic variation is the raw material upon which natural selection works

Mapping the Distance Between Genes Using Recombination Data: Scientific Inquiry

• • Alfred Sturtevant, one of Morgan’s students, constructed a genetic map, an ordered list of the genetic loci along a particular chromosome Sturtevant predicted that

the farther apart two genes are, the higher the probability that a crossover will occur between them and therefore the higher the recombination frequency

Mapping the Distance Between Genes Using Recombination Data: Scientific Inquiry

• a linkage map is a genetic map of a chromosome based on recombination frequencies • distances between genes can be expressed as map units; one map unit, or centimorgan, represents a 1% recombination frequency • map units indicate relative distance and order, not precise locations of genes

RESULTS Recombination frequencies 9% 9.5%

• b-vg recombination frequency = 17% • b-cn recombination frequency = 9%

Chromosome 17%

b cn vg

• genes that are far apart on the same chromosome can

have a recombination frequency near 50%

– such genes are physically linked - but genetically unlinked – they behave as if found on different chromosomes

Short aristae Mutant phenotypes Black body Cinnabar eyes Vestigial wings Brown eyes 0 48.5

57.5

67.0

104.5

Long aristae (appendages on head) Gray body Red eyes Normal wings Wild-type phenotypes Red eyes

• • • Sturtevant used recombination frequencies to make linkage maps of fruit fly genes using methods like chromosomal banding - geneticists can develop cytogenetic maps of chromosomes Cytogenetic maps indicate the positions of genes with respect to chromosomal features

•

Abnormal Chromosome Number

in nondisjunction -pairs of homologous chromosomes do not separate normally during meiosis – as a result, one gamete receives two of the same type of chromosome, and another gamete receives no copy

Meiosis I Nondisjunction

Meiosis I Nondisjunction Meiosis II Non disjunction Gametes

n



1

n



1

n



1

n



1

n



1 Number of chromosomes

n



1 (a) Nondisjunction of homo logous chromosomes in meiosis I

n n

(b) Nondisjunction of sister chromatids in meiosis II

• • • Aneuploidy results from the fertilization of gametes in which nondisjunction

occurred

– offspring with this condition have an abnormal number of a

particular chromosome

a monosomic zygote has only one copy of a particular chromosome – e.g. XO = Turner’s syndrome a trisomic zygote has three copies of a particular chromosome – e.g. 3 chromosome 21 = Down’s syndrome • • • • Polyploidy is a condition in which an organism has more than two complete sets of chromosomes – Triploidy (3n) is three sets of chromosomes – Tetraploidy (4n) is four sets of chromosomes polyploidy is common in plants - but not animals polyploids are more normal in appearance than aneuploids large-scale chromosomal alterations in humans and other mammals often lead to spontaneous abortions (miscarriages) or cause a variety of developmental disorders – plants tolerate such genetic changes better than animals do

Aneuploidy of Autosomal Chromosomes

• •

Down Syndrome (Trisomy 21)

alterations of chromosome number and structure are associated with some serious disorders some types of aneuploidy appear to upset the genetic balance less than others - resulting in individuals surviving to birth and beyond • • • Down syndrome is an aneuploid condition that results from three copies of chromosome 21 it affects about one out of every 700 children born in the United States the frequency of Down syndrome increases with the age of the mother, a correlation that has not been explained

Aneuploidy of Autosomal Chromosomes

• cri du chat (“cry of the cat”) - results from a specific deletion in chromosome 5 – a child born with this syndrome is mentally retarded and has a catlike cry – individuals usually die in infancy or early childhood

Aneuploidy of Sex Chromosomes

• Nondisjunction of sex chromosomes produces a variety of aneuploid conditions – Klinefelter syndrome is the result of an extra chromosome in a male, producing XXY individuals – most common aneuploidy • also known as 47,XXY • 1:500  1:1000 live births • non-disjunction between X and Y chromosomes during meiosis I in spermatogenesis • most are asymptomatic • hypogonadism (decreased endocrine function NOT size)and sterility • gynecomastia • reduced muscle mass, coordination and strength as kids • taller than average • higher incidence (vs. normal males) of breast cancer, autoimmune diseases and osteoporosis

Aneuploidy of Sex Chromosomes

– Monosomy X, called Turner syndrome - produces X0 females • also known as 45, X • all of part of the second X chromosome is absent (e.g. deletion of the p arm) • 1 in 2,000 to 5,000 births • sterile – non-working ovaries • short stature, webbing in the neck, low hairline, low wet • congenital heart disease, hypothyroidism, diabetes, visual problems, many autoimmune diseases, specific cognitive problems • it is the only known viable monosomy in humans

Aneuploidy of Sex Chromosomes

– 48,XXYY and 48,XXXY – 1 in 18,000 to 50,000 live births – 49,XXXXY 1 in 85,000 to 100,000 births

•

Alterations of Chromosome Structure

(a) Deletion A B C D E F G H

breakage of a chromosome can lead to four types of changes in chromosome structure – Deletion removes a chromosomal segment – Duplication repeats a segment – Inversion reverses orientation of a segment within a chromosome – Translocation moves a segment from one chromosome to another

A deletion removes a chromosomal segment.

A B C E F G H (b) Duplication A B C D E F G H A duplication repeats a segment.

A B C B C D E F G H (c) Inversion A B C D E F G H An inversion reverses a segment within a chromosome.

A D C B E F G H (d) Translocation A B C D E F G H M N O P Q R A translocation moves a segment from one chromosome to a nonhomologous chromosome.

M N O C D E F G H A B P Q R

• • • •

Gene Duplications and Deletions

both can arise from unequal crossing over during meiosis often results between repetitive sequences shared between them duplication can also result from replication slippage – DNA polymerase dissociates and reattaches at an incorrect position – copies the same strand of DNA again these are not necessarily bad things

• • • • • •

Translocation

reciprocal translocations involve the exchange of material between non-homologous chromosomes

crossing over between non-homologous chromosomes 1 to 625 newborns usually harmless some may be associated with increased chances of cancer – Philadelphia chromosome – associated with Chronic Myelogenous

Leukemia

– creates two fused gene  fusion protein BCR-Abl – speeds up the cell cycle but increased miscarriages can result in affected individuals • •

Normal chromosome 9 Normal chromosome 22 Translocated chromosome 9 Translocated chromosome 22 (Philadelphia chromosome)

can occur due to errors in mitosis in somatic cells

Reciprocal translocation

– limited to the affected cell type – e.g. CML and Philadelphia chr can also occur in germline cells during meiosis – all cellular progeny affected

Some inheritance patterns are exceptions to standard Mendelian inheritance

• • • • there are two normal exceptions to Mendelian genetics one exception involves genes located in the nucleus the other exception involves genes located outside the nucleus in both cases, the sex of the parent contributing an allele is a factor in the pattern of inheritance – Genetic Imprinting – Organelle Genes

• • •

Genomic Imprinting

for a few mammalian traits, the phenotype depends on

which parent passed along the alleles for those traits

such variation in phenotype is called genomic imprinting

Paternal chromosome Normal

Igf2

allele is expressed.

Maternal chromosome Normal

Igf2

allele is not expressed.

(a) Homozygote Mutant

Igf2

allele inherited from mother Normal-sized mouse (wild type) Mutant

Igf2

allele inherited from father

genomic imprinting involves the silencing of certain genes that are “stamped” with an imprint during gamete production

Normal-sized mouse (wild type)Dwarf mouse (mutant) Normal

Igf2

allele is expressed.

Mutant

Igf2

allele is expressed.

Mutant

Igf2

allele is not expressed.

(b) Heterozygotes Normal

Igf2

allele is not expressed.

Genomic Imprinting

• • • it appears that imprinting is the result of the methylation (addition of —CH 3 ) of the DNA – addition of CH3 to cysteine nucleotides – can result in transcriptional inactivation – the methylation pattern is passed on to progeny through meiosis genomic imprinting is thought to affect only a small fraction of mammalian genes most imprinted genes are critical for embryonic development

• • • •

Inheritance of Organelle Genes

extranuclear genes (or cytoplasmic genes) are found in organelles in the cytoplasm mitochondria, chloroplasts, and other plant plastids carry small circular DNA molecules extranuclear genes are inherited maternally because the zygote’s cytoplasm comes from the egg the first evidence of extranuclear genes came from studies on the inheritance of yellow or white patches on leaves of an otherwise green plant

• Some defects in mitochondrial genes prevent cells from making enough ATP and result in diseases that affect the muscular and nervous systems – inheritance pattern is non-Mendelian – Maternal – only the egg contributes mitochondria to the embryo – e.g. mitochondrial myopathy • type of myopathy associated with abnormal mitochondria • muscle tissue shows “ragged red” fibers with mild accumulations of glycogen • muscle weakness results • numerous types of MMs known – e.g. Leber’s hereditary optic neuropathy • mitochondrial dysfunction results in the degeneration of retinal ganglion cells (neurons in the retina) • loss of central vision