BIOL 1107 - Chromosomal Basis of Inheritance

Physical basis of Mendelian inheritance

-mendel’s proposed “hereditary units” were only theoretical in 1860

-soon biologists saw parallels between chromosome behavior and the behavior of the proposed factors

-around 1902, sutton and boveri and others independently notes these parallels and began to develop the chromosome theory of inheritance

Thomas Hunt Morgan’s Choice of experimental organism

-morgan chose to study drosophila melanogaster, a common species of fruit fly

-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 noted wild type, or normal, phenotypes that were common in the fly population

-traits alternative to the wild type are called mutant phenotypes

-the first mutant morgan discovered was a fly with white eyes instead of the wild-type red eyes

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 F₁ generation all had red eyes

• the F₂ generation showed a 3:1 red to white eye ratio, but only males had white eyes

-morgan reasoned that the white-eyes mutant allele must be located on the X chromosome

-female flies have 2 X chromosomes (XX) while males have one X and one Y (XY)

-morgan’s findings supported the chromosome theory of inheritance

Law of Segregation (during Meiosis)

homologous chromosomes migrate into two different cells. Thus, the two alleles for each gene separate

Law of independent assortment (during meiosis)

the separation of the two alleles of a given gene occurs independently of the separation of the two alleles of other genes. Thus, each cell receives a random collection of alleles (one for each gene)

Sex-linked genes

-morgan’s discovery of a trait that correlated with the sex of flies was key to the development of the chromosome theory of inheritance

-sex-linked genes exhibit unique patters of inheritance

The Chromosomal Basis of Sex

-humans and other mammals have two types of sex chromosomes: a larger X chromosome and a smaller Y chromosome

-a person with two X chromosomes usually develops anatomy we associate with the “female” sex

-”male” properties are associated with the inheritance of one X and one Y

-the X-Y system is not the only chromosomal system of sex determination

-short segments at the ends of the Y chromosomes are homologous with the X, allowing the two to behave like homologs during meiosis in makes

SRY Gene

(sex-determining region on the Y) is a gene on the Y chromosome that is responsible for the development of the testes in an embryo in mammals

What is a sex-linked gene?

-a gene that is located on either sex chromosome

-genes on the Y chromosome are called Y-linked genes

-only 78 genes, coding for about 25 proteins, have been identified on the human Y chromosome

-genes on the X chromosome are called X-linked genes; the human X chromosome contains about 1,100 genes

Inheritance of X-linked genes

-X chromosomes have genes for many characters unrelated to sex

-many Y-linked genes are related to sex determination

-X-linked genes follow a specific pattern of inheritance

-for a recessive X-linked trait to be expressed

• a female needs to 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

Some disorders caused by recessive alleles on the X chromosome in humans

-color blindness (mostly X-linked)

-duchenne muscular dystrophy

-hemophilia

X inactivation in female mammals

-in mammalian females, one of the two X chromosomes in each cell is randomly inactivated during embryonic development

-the inactive X condenses into a Barr body

-if a female is heterozygous for a particular gene located on the X chromosome, she will be a mosaic for that character

-inactivation of an X chromosome involves modification of the DNA and proteins bound to it called histones

-a part of the chromosome contains several genes involved in the inactivation process

-one of the genes there becomes active only on the chromosome what will be inactivated

-the gene is called XIST (X-inactive specific transcript)

Linked genes

-each chromosome has hundreds or thousands of genes (except the Y chromosome)

-genes that are located on the same chromosome tend to be inherited together and are called linked genes

How linkage affects inheritance

-morgan did 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

-the first cross was a P generation cross to generate F₁ dihybrid flies

-the second was a testcross

-the resulting flies had a much higher than expected proportion of the combination of traits seen in the P generation flies (parental phenotypes)

-he concluded that these genes do no assort independently and reasoned that they were on the same chromosome

-nonparental phenotypes were also produced in the testcross, suggesting that the two traits could be separated sometimes (involves genetic recombination)

Genetic recombination

the production of offspring with combinations of traits differing from either parent

Genetic recombination and linkage

the genetic findings of mendel and morgan relate to the chromosomal basis of recombination

Recombination of unlinked genes: independent assortment of chromosomes

-offspring with a phenotype matching on of the parental (P) phenotypes are called parental types

-offspring with nonparental phenotypes (new combination of traits) are called recombinant types or recombinants

-a 50% frequency of recombination is observed for any two genes on different chromosomes

-morgan observed that although some genes are linked, nonparental allele combinations are still produced'

-he proposed that some process must occasionally break the physical connection between genes on the same chromosome

-that mechanism was the crossing over of homologous chromosomes

New combinations of alleles: variation for natural 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

-alfred sturtevant, on of morgan’s students, constructed a genetic map

-he 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

-he used recombination frequencies to make linkage maps of fruit fly genes

-they found that the genes clustered into 4 groups of linked genes (linkage groups)

-the linkage maps, combined with the fact that there are 4 chromosomes in Drosophila, provided additional evidence that genes are located on chromosomes

Genetic map

an ordered list of the genetic loci along a particular chromosome

Linkage map

a genetic map of a chromosome based on recombination frequencies

Map units

-distances between genes; one map until represents a 1% recombination frequency

-map units indicate relative distances and order, not precise locations of genes

Alterations of chromosome number or structure

-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 much better than animals do

Abnormal chromosome number

-nondisjunction

-aneuploidy

-monosomic

-trisomic

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

Aneuploidy

-results from the fertilization of gametes in which nondisjunction occurred

-offsprings with this condition have an abnormal number of a particular chromosome

Monosomic zygote

has only one copy of a particular chromosome

Trisomic zygote

has three copies of a particular chromosome

Polyploidy

-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

Alterations of chromosome structure

-breakage of a chromosome can lead to 4 types of changes in chromosome structure

• deletion - removes a chromosomal fragment

• duplication - repeats a segment

• inversion - reverses orientation of a segment within a chromosome

• translocation - moves a segment from one chromosome to another

Human disorders due to chromosomal alterations

-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

-these surviving individuals have a set of symptoms, or syndrome, characteristic of the type of aneuploidy

Down syndrome (trisomy 21)

-an aneuploid condition that results from three copies of chromosome 21

-it affects about one out of every 830 children born in the US

-the frequency of down syndrome increases with the age of the mother, a correlation that has not been explained

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

-about 1 in 1000 males is XYY; these males do not exhibit any syndrome

-XXX females occur with a frequency of about 1 in 1000

-they are healthy, with no unusual physical features, though they are at risk for learning disabilities

-monosomy X, called Turner syndrome, produces X0 females, who are sterile; it is also the only known viable monosomy in humans

Disorders caused by structurally altered chromosomes

-the syndrome cri du chat (“cry of the cat”) results from a specific deletion in chromosome 5

-a child born with this syndrome is severely intellectually disabled and has a catlike cry; individuals usually die in infancy or early childhood

-certain cancers, including chronic myelogenous leukemia (CML), are caused by translocations of chromosomes

Some inheritance patterns are exceptions to standard Mendelian inheritance

-there are two normally occurring exceptions to Mendelian genetics

-one exceptions involves genes located in the nucleus, and the other involves genes located outside the nucleus

-in both cases, the sex of the parent contributing an allele is a factor in the patter of inheritance

Genomic imprinting

-for a few mammalian traits, the phenotype depends on which parents passed along the alleles for those traits

-such variation in phenotype is called genomic imprinting

-genomic imprinting involves the silencing of certain genes depending on which parents pass them on

-most imprinted genes are on autosomes

Genomic imprinting (mouse example)

-the mouse gene for insulin-like growth factor 2 (lgf2) was one of the first imprinted genes to be identified

-only the paternal allele of this gene is expressed

-it seems that imprinting is the result of the methylation (addition of —CH₃ groups) of cytosine nucleotides

-genomic imprinting may 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, as well as chloroplasts, and other plant plastids carry small circular DNA molecules

-extranuclear genes are inherited maternally because the zygote’s cytoplasm comes from the egg

-some defects in mitochondrial genes prevent cells from making enough ATP and result in diseases that affect the muscular and nervous systems

• ex: mitochondrial myopathy and Leber’s hereditary optic neuropathy