Human Genetics

Human Genetics

NonAutosomal Inheritance

NonAutosomal Inheritance

X-Linked DominantX-linked RecessiveY-linkedMitochondial

The Sex Chromosomes

There is no universal system; can be either genetic or environmental

Humans and fruit flies have the XY genetic system

Y chromosome “single-issue” chromosome designed to determine sex

X chromosome – ‘controlling’For males, it’s the curse of the ‘lone X’Females also prone to certain conditions

The Sex Chromosomes

XX:XY (males heterogametic)

ZZ:ZW (females heterogametic)

Variations include X1X2Y or XY1Y2

Sex-specific chromosomes tend to be small and gene-poor overall, but enriched for genes specifically benefiting the sex that harbours them.

The Sex Chromosomes

In any given species, cytogenetic pattern between homologous chromosomes is similarIn most species, sex chromosomes tend to be heteromorphic (variations in shape, size and gene content)Gene clustering patterns are also different

‘hall of mirrors’ – full of palindromes

50Mb size - ~50 genes

2 domains

Pseudoautosomal region (PAR) – 5%

Non-recombining regions (NRY) – 95%

HMG3 pages 367-372

Y Chromosome

Active genes on the human Y chromosome

Yellow bar, euchromatic NRY (non-recombining region); black bar, heterochromatic portion of NRY; red bars, pseudoautosomal regionsGenes to right: active X-chromosome homologues.Genes to left: lack known X homologues. Genes in red: widely expressed housekeeping genes; genes in black: expressed only in testis genes in green are expressed neither widely, nor testis specifically AMELY (amelogenin Y) is expressed in developing tooth buds, PCDHY (protocadherin Y) is expressed in the brain)

Y chromosome shows the accumulation of spermatogenesis genes and an overall functional decay typical of male-specific chromosomes. Active genes on NRY region classed into 3 types on the basis of tissue expression and homology to the X Class 1: housekeeping genes with ancient homology to X Class 2: testis-specific genes. Class 3: genes variously similar to both classes 1 and 2, as well as other genes that might be decaying towards pseudogene status, or the persistence of which might reflect additional evolutionary factors at work on the Y chromosome. Genes that belong to classes 1 and 2 seem to underlie the medical disorders Turner syndrome and male infertility, respectively.

Y Chromosome Genes

Y-chromosome Inheritance is Paternal

Pedigree of family with Focal Glomerular Sclerosis

Is this trait Y-linked? Not necessarily- other pedigrees indicate it is autosomal. Could also reflect a family exposure only seen in males- this illness is associated with heroin abuse.

Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

Sex and Inheritance

Women have 2 X and men have and XY Homozygosity is possible for an X linked

gene Males with one X chromosome are called

Hemizygous Y chromosomes are also hemizygous. Genes on other chromosomes are affected

by whether an individual is a male or female• Sex influenced• Sex limited

Sex Makes Genetics More Complex

Sex-limited traits- characteristic only appears (or develops) in one of the sexes. Example: Ovary development in females; Sperm

development in males

Sex Influenced Trait- A sex-limited or sex-influenced trait could be encoded by a sex-linked gene, but doesn't have to be. A sex-limited or sex-influenced gene could be located on an autosome.

Cryptorchidism (undescended testicles)

Cryptorchidism is a genetic condition in which one or both testicles fail to descend, and remain in the abdomen. In development, testicles and ovaries develop from the same embryonic tissue, located low in the abdomen, roughly the same position ovaries are located in fully developed females. Late in development, testicles move from their abdominal position, through the inguinal canal into the scrotum, which is essentially a small skin bag which hangs outside the body.

These genes are autosomal; males and females each carry two alleles. Temperature in the abdomen is too high to develop viable sperm, so males are sterile and greater cancer risk.

Only males can possible exhibit the condition, because only males show the normal condition for testicle behavior and position.

Male Pattern Baldness

What have you learned about this trait?Not as well characterized as textbooks imply.

Pattern Baldness often incorrectly identified as X-linked

Males can inherit baldness from either parent, but when a son gets it from his father, both father and son are bald. No one notices, because we expect sons to look like their fathers.

If a son loses his hair and his father doesn’t, that’s striking, and people concluded (correctly) is that Junior inherited baldness from his mother.

But, with X-linkage, sons always inherit traits from their mothers and never from their fathers.

Sex Influenced: Pattern Baldness

This trait may be polygenic [OMIM 109200]The locus with strongest evidence of linkage

was mapped to 3q26 (AGA1) with a nonparametric linkage (NPL) score of 3.97 (P = 0.00055). The other 3 regions were in chromosomes 11q22, 18q11, and 19p13. Hillmer 2008)

Consider two alleles, “bald” and “non-bald.” The behaviors of the products of these genes

are highly influenced by the hormones in the individual, particularly by the hormones testosterone.

Sex Influenced: Pattern Baldness

In the presence of high levels of testosterone, the baldness allele is dominant (males).

In the presence of low levels of testosterone, this allele is recessive (females).

All humans have testosterone, but males have much higher levels of this hormone than females do. Dominance only matters in the heterozygote, so heterozygous

males experience hair loss and heterozygous females don’t. Homozygous females may experience no more than a thinning

of their hair, although some may develop bald spots or have receding hairlines.

Females with polycystic ovaries show pattern baldness http://query.nytimes.com/gst/fullpage.html?res=9802e1

d91638f935a25752c1a9659c8b63&scp=2&sq=male%20pattern%20baldness&st=cse

X-Linked Dominant Genes

The key for determining if a dominant trait is X-linked or autosomal is to look at the offspring of the mating of an affected male and a normal female.

If the affected male has an affected son, then the disease is not X-linked. All of his daughters must also be affected if the disease is X-linked.

X-Linked Dominant Inheritance

Rules for X-Linked Dominance

The trait is never passed from father to son. All daughters of an affected male and a normal female

are affected. All sons of an affected male and a normal female are normal.

Matings of affected females and normal males produce 1/2 the sons affected and 1/2 the daughters affected.

Males are usually more severely affected than females. The trait may be lethal in males.

In the general population, females are more likely to be affected than males, even if the disease is not lethal in males.

X-linked Dominance with Lethality

X-Linked Recessive Inheritance

Sex Linked Recessive Punnet Squares Are Useful

http://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookhumgen.htmlImages from Purves et al., Life: The Science of Biology, 4th Edition, by Sinauer Associates and WH Freeman

X-Linked Recessive Rules

As with any X-linked trait, the disease is never passed from father to son.

Males are much more likely to be affected than females. If affected males cannot reproduce, only males will be affected.

All affected males in a family are related through their mothers.

Trait or disease is typically passed from an affected grandfather, through his carrier daughters, to half of his grandsons.

Glucose 6 Phosphate Dehydrogenase Deficiency

X-linked Recessive Trait

What happened for the Proband?

He must have inherited the disease from his mother, whose father had the disease.

Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

Question

What is the probability person II-5 has inherited the trait from her mother?

What is the Probability she passes the trait on to her son?

What is the probability she passes the trait on to her daughter?

Answer

What is the probability person II-5 has inherited the trait from her mother? 50%

What is the Probability she passes the trait on to her son? 50% x 50% [25%]

What is the probability she passes the trait on to her daughter? 50% x 50% [25%]

X-linked Traits are common in men and rare in women

Red-Green color blindness: X-linked trait. It is easy to explain the phenotype and it's

relatively common.7% to 10% of men are carriersCalculations predict 0.49% to 1% for women. It's commonness is possibly attributable to it not

being a serious disability in most cases and an possible advantage in some situations

Mitochondrial Diseases

In 1963, researchers discovered mitochondria have their own DNA (mtDNA), different than the nuclear DNA (nDNA) found in the cells' nucleus.

Mitochondrial and metabolic medical conditions include more than 40 different identified diseases with different genetic features.

The common factor among these diseases is that the mitochondria are unable to completely burn food and oxygen in order to generate energy.

09_01.jpg

Mitochondrial DNA

Multicopy (466-806 per cell)16,569 bp length and 0.68mM diameterGenes lack intronsMaternally inheritedSequenced in 1981 (Nature,1981, 290:457-65)Mutation rate ~1/33 generationsHeteroplasmy (original and mutated forms co-

exist)More stable for forensic analysis

Mitochondrial Inheritance is Maternal

Ovum, originating in the female, have about 100,000 copies of mitochondrial DNA.

Sperm, originating in the male, has fewer than 100 copies, and these are probably lost at fertilization.

Virtually all of your mitochondria come from your mother.

Affected fathers produce no affected offspring, while the offspring of affected mothers are all affected.

Mitochondria make ATP

Mitochondrial Inheritance

Mitochondrial Eve

(MEERF) Mitochondrial Encephalomyopathy with ragged-red muscle fibers

Note mother passes trait to all children but the son doesn’t pass it at all and all the daughters pass it on.

Also note the variability in the symptoms as well as their severity

Principles of Medical Genetics 1998 Gelehrter et al. Lippincott Williams & Wilkins

X-Linked Trait

What chance person III-6 can pass on the trait to sons? Daughters?

What chance person III-4 inherited the trait? What chance Person III-3?