Genes, Chromosomes, and Human Genetics

Genetic Linkage and Recombination The principles of linkage and recombination were determined with Drosophila Recombination frequency can be used to map chromosomes Widely separated linked genes assort independently

Chromosomes Genes Sequences of nucleotides in DNA Arranged linearly in chromosomes

Linked Genes Genes carried on the same chromosome Linked during transmission from parent to offspring Inherited like single genes Recombination can break linkage

Drosophila melanogaster Fruit fly Model organism for animal genetics Compared to Mendel’s peas Used to test linkage and recombination

Gene Symbolism Normal alleles (wild-type) Wild-type Mutant Usually most common allele Designated by “+” symbol Usually dominant Wild-type Mutant + = red eyes pr = purple + = normal wings vg = vestigial wings

Genetic Recombination Alleles linked on same chromosome exchange segments between homologous chromosomes Exchanges occur while homologous chromosomes pair during prophase I of meiosis

Evidence for Gene Linkage

Linked genes Genes that are close together on the same chromosome Belong to the same linkage group

Linkage and Recombination Linkage; genes are inherited together Crossing over produces recombination – breaks up the association of genes that are linked

Notation for linkage AABB X aabb

Recombination Frequency Amount of recombination between two genes reflects the distance between them The greater the distance, the greater the recombination frequency Greater chance of crossover between genes

Recombination Frequency

Mapping of Genes Where is the gene is located on a chromosome? Linkage maps – A chromosome map; abstract based on recombinant frequencies Physical maps – Mapping the positions of cloned genomic fragments

Linkage Maps First genetic map Alfred Sturtevant in the lab of Thomas Hunt Morgan Observed that some pairs of genes do not segregate randomly according to Mendel’s principle of independent segregation Proposed genes were located on the same chromosome Variation in the strength of linkage determined how genes were positioned on the chromosome

Chromosome Maps Recombination frequencies used to determine relative locations on a chromosome Linkage map for genes a, b, and c:

Map: Drosophila Chromosome

Predicting the outcomes of crosses with linked genes Determining proportions of the types of offspring requires knowing the RF

RF = 16%

Gene mapping with RFs Genetic maps Calculated by RFs Measured in map units or centimorgans (cM) RF can not exceed 50%, at 50% cannot distinguish between genes on the same or different chromosomes Double crossovers – underestimate distance

Recombination Occurs Often Widely separated linked genes often recombine Seem to assort independently Detected by testing linkage to genes between them

Sex-Linked Genes In both humans and fruit flies, females are XX, males are XY Human sex determination depends on the Y chromosome

Sex-Linked Genes Sex-linked genes were first discovered in Drosophila Sex-linked genes in humans are inherited as they are in Drosophila Inactivation of one X chromosome evens out gene effects in mammalian females

Sex Chromosomes Sex chromosomes determine gender X and Y chromosomes in many species XX: female XY: male Other chromosomes are called autosomes

Sex Determination in Humans

Human Sex Chromosomes Human X chromosome Human Y chromosome Large (2,350 genes) Many X-linked genes are nonsexual traits Human Y chromosome Small (few genes) Very few match genes on X chromosome Contains SRY gene Regulates expression of genes that trigger male development

Conclusions At least one copy of X is required for human development Male-determining gene is on the Y; a single copy produces a male regardless of the number of X’s Absence of Y is female Genes affecting fertility are on the X and Y >X’s produces physical and mental disabilities

Sex determination in humans Sex reversed individuals XX males and XY females Clues that there is a gene on the Y that determines maleness

Proof that SRY is the male-determining gene Experiment in mice

SRY gene When mouse sry was injected into the genome of a XX zygote, the transgenic female mice developed as males (sterile)

Function of SRY DNA binding protein Initiates a sex switch – transcription factor Initiates a sex switch – Acts on genes in the undifferentiated gonad, transforming it into a testis Once the testis has developed testosterone is produced for male secondary sex characteristics If no SRY, the gonad develops into an ovary

Androgen Insensitivity If the androgen receptor (AR) is deleted or null in function then testosterone can not act and no maleness results Results from a mutation in the AR

Evolution of the Y BioInteractive's Animation Console: Y Chromosome

Hey! Females have two X’s and males only have one! Females are superior?

Dosage Compensation X-inactivation Mary Lyon Barr Body

Dosage Compensation X-inactivation XXY males have a Barr body XO females have none Barr body is the inactivated X

Dosage Compensation X-inactivation In human females an X chromosome is inactivated in each cell on about the 12th day of embryonic life

Dosage Compensation X-inactivation X-inactivation is random in a given cell Heterozygous females show mosaicism at the cellular level for X-linked traits

How is the X chromosome inactivated?

How is the X chromosome inactivated? X inactivation specific transcript (Xist) gene

X-inactivation center (XIC) Gene for XIST Encodes an XIST RNA which is expressed solely from the inactive X-chromosome Coats the inactive X and is involved in gene silencing Several genes remain active (PAR and others)

Calico Cats Heterozygote female (no male calico cats)

Barr Body Tightly coiled condensed X chromosome Attached to side of nucleus Copied during mitosis but always remains inactive

Sex Linkage Female (XX): 2 copies of X-linked alleles Male (XY): 1 copy of X-linked alleles Only males have Y-linked alleles

Sex Linkage Males have only one X chromosome One copy of a recessive allele results in expression of the trait Females have two X chromosomes Heterozygote: recessive allele hidden (carrier) Homozygote recessive: trait expressed

Eye Color Phenotypes in Drosophila Normal wild-type: red eye color Mutant: white eye color

Evidence for Sex-Linked Genes

Human Sex-Linked Genes Pedigree chart show genotypes and phenotypes in a family’s past generations X-linked recessive traits more common in males Red-green color blindness Hemophilia: defective blood clotting protein

Inheritance of Hemophilia In descendents of Queen Victoria of England

Color Blindness in Humans

Try this problem color-blind female color-blind male Red-green color blindness is X-linked recessive. A woman with normal color vision has a father who is color-blind. The woman has a child with a man with normal color vision. Which phenotype is NOT expected? color-blind female color-blind male noncolor-blind female noncolor-blind male

Chromosomal Alterations That Affect Inheritance Most common chromosomal alterations: deletions, duplications, translocations, and inversions Number of entire chromosomes may also change

Chromosomal Alterations Deletion: broken segment lost from chromosome Duplication: broken segment inserted into homologous chromosome

Chromosomal Alterations Translocation: broken segment attached to nonhomologous chromosome Inversion: broken segment reattached in reversed orientation

c. Reciprocal translocation One chromosome Nonhomologous chromosome Reciprocal translocation Figure 13.11 Chromosome deletion, duplication, translocation (a reciprocal translocation is shown), and inversion. Fig. 13-11c, p. 266

Nondisjunction Failure of homologous pair separation during Meiosis I

Nondisjunction Failure of chromatid separation during Meiosis II

b. Nondisjunction Extra chromosome (n + 1) Missing chromosome (n – 1) Normal (n) Figure 13.12 Nondisjunction during (a) the first meiotic division and (b) the second meiotic division. Normal (n) Meiosis I Meiosis II Gametes Nondisjunction during the second meiotic division produces two normal gametes, one gamete with an extra chromosome and one gamete with a missing chromosome. Fig. 13-12b, p. 267

Changes in Chromosome Number Euploids Normal number of chromosomes Aneuploids Extra or missing chromosomes Polyploids Extra sets of chromosomes (triploids, tetraploids) Spindle fails during mitosis

Aneuploids Abnormalities usually prevent embryo development Exception in humans is Down syndrome Three copies of chromosome 21 (trisomy 21) Physical and learning difficulties Frequency of nondisjunction increases as women age

Down Syndrome

a. 1 2 3 4 5 6 7 8 9 10 11 12 Figure 13.13: Down syndrome. (a) The chromosomes of a human female with Down syndrome showing three copies of chromosome 21 (circled in red). 13 14 15 16 17 18 19 20 21 22 23 Fig. 13-13a, p. 268

Incidence of Down syndrome b. Incidence of Down syndrome per 1000 births Figure 13.13: Down syndrome. (b) The increase in the incidence of Down syndrome with increasing age of the mother, from a study conducted in Victoria, Australia, between 1942 and 1957. Mother’s age Fig. 13-13b, p. 268

Aneuploidy of Sex Chromosomes

Aneuploidy of Sex Chromosomes

Human Genetics and Genetic Counseling In autosomal recessive inheritance, heterozygotes are carriers and homozygous recessives are affected by the trait In autosomal dominant inheritance, only homozygous recessives are unaffected

Human Genetics and Genetic Counseling Males are more likely to be affected by X-linked recessive traits Human genetic disorders can be predicted, and many can be treated

Modes of Inheritance Autosomal recessive inheritance Autosomal dominant inheritance X-linked recessive inheritance

Pictorial representation of a family history Pedigree Analysis I Pictorial representation of a family history

Autosomal Recessive Inheritance Males or females carry a recessive allele on an autosome Heterozygote Carrier No symptoms Homozygote recessive Shows symptoms of trait

Autosomal recessive traits Appear In equal frequency in both sexes Only when a person inherits two alleles for the trait (one from each parent) To skip generations (Heterozygotes unaffected) Ex. Tay Sachs Tay-Sachs disease

Autosomal Recessive Inheritance

Cystic Fibrosis

Autosomal Dominant Inheritance Dominant gene is carried on an autosome Homozygote dominant or heterozygote Show symptoms of the trait Homozygote recessive Normal

Autosomal dominant traits Appear In equal frequency in both sexes Both sexes can transmit the trait Does not skip generations unless acquired as a new mutation Ex. Familial hypercholesterolemia OMIM - HYPERCHOLESTEROLEMIA, AUTOSOMAL DOMINANT

Autosomal Dominant Inheritance

X-Linked Recessive Inheritance Recessive allele carried on X chromosome Males Recessive allele on X chromosome Show symptoms Females Heterozygous carriers, no symptoms Homozygous, show symptoms

X-linked recessive traits Appear more frequently in males Passed from unaffected female to males Skips generations Ex. Hemophilia A Hemophilia A

X-Linked Recessive Inheritance

X-linked dominant traits Appear more frequently in females Affected men pass the trait to all of their daughters and none of their sons Do not skip generations Ex. Hypophosphatemia OMIM - HYPOPHOSPHATEMIA, X-LINKED

Y-linked traits Appear Ex. Hairy ears OMIM - HAIRY EARS, Y-LINKED Only males are affected Affected men pass the trait to all of their sons Do not skip generations Ex. Hairy ears OMIM - HAIRY EARS, Y-LINKED

Genetic Counseling Identification of parental genotypes Construction of family pedigrees Prenatal diagnosis Allows prospective parents to reach an informed decision about having a child or continuing a pregnancy

Genetic Counseling Techniques Prenatal diagnosis tests cells for mutant alleles or chromosomal alterations Cells obtained from: Embryo Amniotic fluid around embryo (amniocentesis) Placenta (chorionic villus sampling) Postnatal genetic screening Biochemical and molecular tests

Prenatal genetic testing Ultrasonography Aminocentesis CVS – chorionic villus sampling Karyotype Maternal blood tests PGD

Postnatal genetic testing Newborn screening, ex. PKU Heterozygote screening, ex. Tay Sachs Presymptomatic testing, ex. Huntington

Interaction between Sex and Heredity

Cytoplasmic inheritance Characteristics encoded by genes in the cytoplasm Cytoplasmic organelles inherited from the egg Extensive phenotypic variation – no mechanism to ensure proper segregation Ex. Mitochondrial genes

Matrilineal inheritance

Russian Revolution July 16, 1918 a firing squad executed the tsar, his family, and attendants Skeletal remains found in 1979

Are the skeletal remains actually Nicholas II and his family? Evidence: Younger brother’s Grand Duke Georgij femur and tibia Blood-stained hankie from Nicholas II Hair clippings from Nicholas II

Discrepancy in the number of skeletons Tsar, his wife, 5 children, 3 servants and physician 9 skeletons were found – how to explain the discrepancy?

Nuclear DNA Nuclear DNA from the skeletons established that the skeletons were a family group The DNA matched a father and three daughters

How to prove the skeletons were those of the royal family?

Prince Philip’s DNA Scientists used Prince Philip’s mitochondrial DNA to prove that the skeletons were the remains of Alexandra and her three daughters Why mitochondrial DNA?

To establish identity of Nicholas II To establish the identity of Nicholas II scientists needed living relatives – why?

Relatives Xenia – direct female descendent of the tsar’s sister James – descends from a line that is connected to Nicholas II through his grandmother

Not a perfect match Xenia = James but does not match Nicholas II T at position 16,169 Nicholas there is a mixture of C and T How can this be?

Nicholas II other brother Georgij Exhumation of Nicholas II other brother Georgij had an examination of his mitochondrial DNA also contained the heteroplasmy confirming the remains were that of Nicholas II

Nontraditional Patterns of Inheritance Cytoplasmic inheritance follows the pattern of inheritance of mitochondria or chloroplasts In genomic imprinting, the allele inherited from one of the parents is expressed while the other allele is silent

Cytoplasmic Inheritance Genes carried on DNA in mitochondria or chloroplasts Cytoplasmic inheritance follows the maternal line Zygote’s cytoplasm originates from egg cell

Cytoplasmic Inheritance Mutant alleles in organelle DNA Mendelian inheritance not followed (no segregation by meiosis) Uniparental inheritance from female

Human Mutations in Mitochondrial Genes

Genomic Imprinting Expression of an allele is determined by the parent that contributed it Only one allele (from either father or mother) is expressed Other allele is turned off (silenced) Often, result of methylation of region adjacent to gene responsible for trait