Chromosomal Basis of Inheritance Chromosome Theory Chromosome number

Chromosomal Basis of Inheritance

Chromosome Theory • Chromosome number is constant within the species but varies among. • Chromosome theory emerged right after Mendel’s work by Sutton and Boveri (1902).

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Sex Chromosomes in Humans and Drosophila – Females have two X, while males have X and Y. – Producing two kinds of gametes, so males are heterogametic. – Producing one kind of gamete, so females are homogametic. – Random fusion of gametes produces an F 1 that is ½ female (XX), and ½ (XY).

Fig. 11. 3 Parental Cross F 1 x F 1 Males are hemizygous (w/Y) because there is no homologous gene on the Y chromosome.

Morgan’s student Calvin Bridges: 1. Discovered 1/2000 are either white-eyed female or red-eyed male. 2. Hypothesized that X chromatids failed to separate in meiosis resulting in non-disjunction. 3. Possible outcomes (aneuploidy = chromosomes absent or present in unusual number). 1. YO die (no X chromosome) 2. XXX die (extra X) w+ 3. X O red-eyed sterile males (no X from mother) 4. Xw. Y white-eyed females (two X from mother)

Fig. 11. 5 Nondisjunction in meiosis involving the X chromosome Peter J. Russell, i. Genetics: Copyright © Pearson Education, Inc. , publishing as Benjamin Cummings.

Aneuploidies 1. 2. 3. 4. YO XXX Xw+O Xw. Y die (no X chromosome) die (extra X) red-eyed sterile males (no X from mother) white-eyed females (two X from mother)

X-linked recessive: hemophilia A • Lacks a clotting factor • Queen Victoria either a carrier or a mutation occurred in germ cells. – If father to son inheritance, not X-linked recessive – Many more males (females have 2 doses of X) – Homozygous mutant mother, all sons inherit the trait – Carier mothers lead to 1: 1 ratio – Carrier female x normal male all daughters normal; half sons have trait – Homozygous normal female x affected male all normal

Sex Determination in Drosophila • An X-chromosome-autosome balance system is used. • Drosophila has 3 pairs of autosomes, and one pair of sex chromosomes. – XX is female. – XY is male. – However, Y does not determine sex.

XXY fly is female, XO is male. • The sex of the fly results from the ratio of the number of X chromosomes (X) to the number sets of autosomes (A): – In a normal diploid male Drosophila: • A=2 • X=1 • X: A ratio = 0. 5 – In a normal diploid female Drosophila: • A=2 • X: A ratio = 1

Aneuploidy • When X: A ratio is 1, the fly is female. • When X: A ratio is 0. 5, the fly is male. • A ratio between 0. 5 and 1 results in a sterile intersex fly with male and female traits. • Dosage compensation in Drosophila results in doubling of expression of X-linked genes in males, so the level of transcription equalized.

Sex Determination in Drosophila • The Sxl gene is turned on in females, while it remains off in males. • The presence of Sxl protein induces productive splicing of m. RNAs from transformer (tra). • Tra protein expressed from the female tra m. RNAs together with Tra 2 (which is expressed in both sexes) activate the female splicing of m. RNAs from the gene doublesex (dsx). • The Dsxf protein represses the transcription of genes required for male development and activates those required for female development.

What happens when Sxl is absent? • tra m. RNA is spliced in a nonproductive pattern, which includes exon sequences containing a stop codon. • No Tra protein is expressed from the male tra. • as a consequence dsxm RNA is spliced in the male pattern. The Dsxm protein translated from this m. RNA represses female development and promotes male. X X

Dosage Compensation in Drosophila • In Drosophila, Sxl regulates dosage compensation in two ways. – Indirect: in females Sxl represses the translation of a gene called male-specific lethal-2 (msl-2) which is required to hyperactivate expression of X-linked genes in males. – Direct: Sxl directly regulates expression of some Xlinked genes. Because the processes of sex determination and dosage compensation are coupled in Drosophila, changes in chromosome number also cause sex specific lethality rather than just sexual transformation.

Hermaphrodites • C. elegans can be either a male or a "hermaphrodite, " producing both sperm and eggs. • Although hermaphrodites can mate with males, they can also self-fertilize.

Sexual Dimorphism • Hermaphrodites are essentially female animals that produce sperm during larval development and oocytes during adulthood. • They have sex-specific set of neurons and muscles that control egg laying. • Male worms are slimmer and have tails equipped with structures that allow the male to detect and inseminate an appropriate mate.

If hermaphrodites can reproduce themselves, then why bother to have males? • when the environment is unstable • when the species is subject to stress • new combinations of genes are introduced into the population. • Normally hermaphrodites spawn other hermaphrodites. But when hermaphrodites are stressed (e. g, warm environment, they produce males). • And they do it by dropping an X chromosome.

Sex Determination in Worms • Genetically determined. • Instead of having an X and a Y, worms have only an X to work with. • The ratio of X chromosomes to sets of autosomes causes XX animals to become hermaphrodites and XO animals to become males. • When hermaphrodites self-fertilize, they produce other hermaphrodites. • Stress may lead to males: an X gets lost in the genetic shuffle, a male is born.

How does a worm count how many Xs he or she has? • xol-1, the master switch gene that controls sex determination in the worm. When xol-1 is active, it produces XOL-1 protein, which initiates male development; when the gene is switched off, and XOL-1 is absent, a hermaphrodite develops.

Is there a problem with gene dosage? • Because hermaphrodites have two Xs, they also have a double dose of every gene on the X, even the ones that have nothing to do with sex. • Genes make proteins, so hermaphrodites stand to produce twice as much X-encoded protein as males. • Such genetic imbalance can be harmful in any organism: Down's syndrome in humans is caused by having an extra copy of chromosome 21. For worms, the extra X can be lethal.

Dosage Compensation • To equalize their X proteins, hermaphrodites turn down the activity of all the genes on the X chromosome at once by 50%. • In Drosophila instead of reducing the gene activity in the XX female, flies double the activity of all the genes expressed on the male's single X.

Once upon a time • There was a perfectly normal pair of chromosomes; X and Y diverged about 300 million years ago.

What did these ancestral chromosomes look like? • Although the Y houses a handful of genes that make a male, about half the genes that reside on this chromosome are also found on the X. • They encode proteins that take care of general housekeeping and cellular maintenance tasks, to be shared by both sexes. • Now these genes are recognized as living fossils, representatives of the genes that were present on the pair of identical chromosomes from which X and Y sprang.

X and Y chromosomes

Evolution of X and Y • Y acquired SRY, or a gene that performed a similar role in sex determination. • At some point, X and Y lost the ability to recombine. • The two Xs can still partner with one another and exchange DNA. • But with no proper partner, the Y began to unravel, losing many of its genes. Such genetic decay would explain why the Y chromosome has only 50 or so genes while the X supports about 1500.

Y chromosome is more than a rotting X? • It harbors genes that are male specific. • Some of these genes, it appears, used to be located on various autosomes; they relocated to their home on the Y some 30 to 50 million years ago. • This genetic migration may represent an opportunistic move—perhaps the Y provided a safe haven for genes that benefit males but are inconsequential or even somehow harmful to females.

Dosage Compensation for Xlinked Genes in Mammals • Gene dosage: how much of a gene is produced per cell/organism. • It varies between sexes in mammals because: – Females have 2 Xs and males have only 1 X.

Barr Body • It is a condensed and mostly inactivated X chromosome. Lyonization of one chromosome leaves one transcriptionally active X, equalizing the dose between sexes. • An X is randomly chosen in each cell for inactivation early in development (in humans, 16 days postfertilization).

Genetic Mosaics • Descendants of that cell will have the same X inactivated, making female mammals genetic mosaics. Examples are: – Calico cats, in which differing descendant cells produce patches of different color in the animal. – Women heterozygous for an X-linked allele responsible for sweat glands, who have a mosaic of normal skin and patches lacking sweat glands (anhidrotic ectodermal displasia).

Lyonization • After Mary Lyon (1961). It allows extra sex chromosomes to be tolerated well. No such mechanism exists for autosomes, and so an extra chromosome is usually lethal. • The number of Barr bodies is the number of X chromosomes minus 1. • Cis-acting factors (acting on the same chromosome) encoded by the X must be important in this process. Likewise, transacting factors (acting on different chromosomes) encoded by chromosomes other than the X or Y were presumed to be equally important.

In germ cells • The inactivation is reversed during germ cell formation so that all haploid oocytes contain an active X chromosome and can express X-linked gene products.

X-inactivation • It involves three steps: – Chromosome counting (determining the number of Xs in the cell). – Selection of an X for inactivation. – Inactivation itself.

Counting chromosomes • Involves the X-inactivation center (XIC in humans, and Xic in mice). Experiments in transgenic mice show that: – Inactivation requires the presence of at least two Xic sequences, one on each X chromosome. – Autosomes with an Xic inserted are randomly inactivated, showing that Xic is sufficient for chromosome counting and initiation of lyonization.

Selection of X • Selection of an X for inactivation is made by the X-controlling element (Xce) in the Xic region. There are different alleles of Xce, and each allele has a different probability that the X chromosome carrying it will be inactivated.

Inactivation • Xist is required. It is expressed from the inactive X. – The Xist gene transcript is 17 -kb. Although it has no ORFs, it receives splicing and a poly(A) tail. – During X inactivation, this RNA coats the chromosome to be inactivated and silences most of its genes.

Sex Determination in Mammals • In placental mammals, cells with a Y chromosome uniquely produce testisdetermining factor, which sets the switch to male development. – Testis-determining factor causes formation of testes instead of ovaries. – All other sex differences result from the specific gonads (either ovaries or testes) and so testis formation governs development of maleness.

Sex Determination in Humans • In humans male and female embryos are identical until the seventh week of development. • Sexual differentiation begins when a sexdetermining gene on the Y chromosome directs the bipotential gonad to turn into testes rather than ovaries. • In the absence of a Y chromosome, the embryo will develop female structures.

SRY (sex-determining region Y) • SRY gene is in that region of the Y chromosome that is deleted, and has many of the expected properties: – It is expressed only in the gonadal ridges of the embryo just before testes form. – Microinjection of the Sry gene into XX mouse cells produced normal males.

What is SRY? • The SRY/Sry gene product is likely a transcription factor, regulating the expression of other genes involved in testis determination.

Genotypic sex determination Evidence for the Y chromosome mechanism: 1. 2. Y chromosome confers maleness and determines sex. Verified by studies of non-disjunction aneuploidy: XO ü ü “Turner Syndrome” Female Sterile 1/10, 000 (most XO fetuses die before birth). Survivors show below average height, poorly developed breasts, and immature sexual organs XXY “Klinefelter Syndrome” ü Male ü 1/1000 ü Above average height, under-developed testes, and breast development in ~50% XYY-Male with above average height, fertility problems. XXX-Female, normal though sometimes less fertile.

Studies of Sex Reversal • In XX males, a small fragment of Y is translocated to an X. • Some XY females have a deletion of the same region of Y.

XY females • In the 1960 s, the International Olympic Committee (IOC) instituted genderverification tests to rule out the possibility of males passing as females in Olympic competition. Subsequently, some female athletes were disqualified from competition because of the results of these tests.

XY individuals are phenotypically female • XY females are sex-reversed individuals, but they are usually unaware of their genotype. Hormone levels and muscle mass are typically female. • The embryo proceeded down the path to becoming female because the male sex-determining factor might have been absent. – SRY could have been deleted from the Y chromosome. – Another possibility is that SRY was present and functional, but cells were unable to respond to the onset of male hormones (androgen insensitivity). – XY females have been raised as females.

Tests for XY • An early gender-verification test examined the inactivated X chromosome (known as the Barr body). • The next step in testing was karyotyping. • Later tests looked for the presence of the SRY gene. • What is the validity of using these tests to determine athletic eligibility? • Would an XY female necessarily have an advantage over an XX female?

Is it discrimination? • In June 1999 the IOC decided to discontinue the gender-verification practice on a trial basis for the 2000 Olympics in Sydney.

Birds, butterflies, moths, and some fish • Male is the homogametic sex (ZZ), whereas the female is heterogametic (ZW). Z-linked genes behave like Xlinked genes in mammals, but the sexes are reversed.

Plants • The arrangement of sex organs varies: – Dioecious species (e. g. , gingko) have plants of separate sexes, one with male parts, the other with female. – Monoecious species have male and female parts on the same plant. • Perfect flowers (e. g. , rose, buttercup) have both types of parts in the same flower. • Imperfect flowers (e. g. , corn) have male and female parts in different flowers on the same plant.

Environmental Sex Determination • A few species use environmental sex determination systems, in which environmental factors affect the sex of progeny. • Some types of turtles are an example. – Eggs incubated above 32 C develop into females, whole those below 28 become males. Eggs between these temperatures produce a mix.