Chromosomal Basis of Inheritance Chapter 15 Timeline 1860s

Chromosomal Basis of Inheritance Chapter 15

Timeline 1860’s Mendel proposed discrete inherited factors segregate and assort independently during gamete formation 1875 cytologists work out mitosis 1890 cytologists work out meiosis 1900 Coffens, de Vries, and van Seysenegg independently rediscover segregation and independent assortment 1902 cytology and genetics converge w Sutton, Boveri who notice parallels between meiosis and Mendel’s factors

Thomas Hunt Morgan Traced gene to a specific chromosome (early 1900 s) Used Drosophila melanogaster Flies are easily cultured, breed prolifically, short generation time, only 4 pr of chromosomes visible w light microscope Identified X and Y chromosomes Discovered sex linked genes

Laboratory Research on Fruit Flies Bred flies and observed characters for a year before finding a single male fly with white eyes Wild type is normal or most frequently observed phenotype (red eyes brown body straight wings) Mutant phenotypes: alternatives to the wild types which are due to mutations of the wild type gene

Wild type fruit flies female

Sex Linked Genes Deduced eye color linked to sex and gene for eye color is located only on the X chromosome If only on X, then females XX carry two copies of the gene and males have only one If recessive, females must be homozygous to show trait Sex-linked genes: located on sex chromosomes (X or Y) X is larger and has more genes on it; both genders may be affected

Fly Life Cycle

Red Eyes White Eyes

Linked genes and independent assortment Linked genes are located on the same chromosome and tend to be inherited together unless there is a crossover Linked genes do not assort independently; move together through meiosis and fertilization Dihybrid cross will not result in new phenotypes (unless there is a crossover) or in phenotypic ratio of 9: 3: 3: 1

Genetic Recombination Offspring with new combinations of traits different from those combinations found in the parents Results from events of meiosis (crossovers) and random fertilization When 50% of offspring are recombinants, indicates that the two genes assort randomly

Notation for fly characters For a given character - the gene takes its symbol from the first mutant discovered For black bodies - b For short wings - vg (for vestigial) The normal phenotype is called wild type & is indicated with a superscript + For wild type - gray bodies - b+ For wild type - normal wings - vg+ If mutant is dominant, then uppercase letter curly wings=Cy, wild type=Cy+

Fig. 15. 4 Copyright © 2002 Pearson Education, Inc. , publishing as Benjamin Cummings

Gray, wild wings crossed w black, vestigial wings Recombination frequency 391 recomb/2300 total offspring x 100= 17% phenotypes genotypes Unlinked expected Linked expected Actual results Black body, b vg+ /b vg wild wings ----- 206 1150 965 Gray body, wild wings 575 b+vg+ /b vg 575 Black body, b vg/ b vg vest. wings 575 1150 944 Gray body, vest. wings 575 ------ 185 b+ vg/b vg

Morgan reasoned that body color and wing shape are usually inherited together because their genes are on the same chromosome. Copyright © 2002 Pearson Education, Inc. , publishing as Benjamin Cummings

Crossing over can unlink genes Morgan’s results from this dihybrid testcross showed that the genes were neither unlinked nor totally linked If unlinked, 1: 1: 1: 1 ratio of all possible phenotypic combinations If completely linked, then 1: 1 of parent types only Morgan proposed mechanism to break linkage: crossing over

Mapping linear sequences on genes Some genes linked more tightly than others b and vg frequency is 17% b and cn (cinnabar eyes) is 9% Sturtevant: probability of crossing over is directly proportional to distance between them one map unit is 1% : one centimorgan If recombination frequency is 50%, they are not distinguishable from unlinked genes

Sturtevant used the test cross design to map the relative position of three fruit fly genes, body color (b), wing size (vg), and eye color (cn). The recombination frequency between cn and b is 9%. The recombination frequency between cn and vg is 9. 5%. The recombination frequency between b and vg is 17%. The only possible arrangement of these three genes places the eye color gene Fig. 15. 6 between the other two. Copyright © 2002 Pearson Education, Inc. , publishing as Benjamin Cummings

Recombination Frequencies Sturtevant expressed the distance between genes, the recombination frequency, as map units. One map unit (sometimes called a centimorgan) is equivalent to a 1% recombination frequency. You may notice that the three recombination frequencies in our mapping example are not quite additive: 9% (b-cn) + 9. 5% (cn-vg) > 17% (b-vg). This results from multiple crossing over events. A second crossing over “cancels out” the first and reduced the observed number of recombinant offspring. Genes farther apart (for example, b-vg) are more likely to experience multiple crossing over events.

Some genes on a chromosome are so far apart that a crossover between them is virtually certain. In this case, the frequency of recombination reaches is its maximum value of 50% and the genes act as if found on separate chromosomes and are inherited independently. In fact, several genes studies by Mendel are located on the same chromosome. • For example, seed color and flower color are far enough apart that linkage is not observed. • Plant height and pod shape should show linkage, but Mendel never reported results of this cross.

Genes located far apart on a chromosome are mapped by adding the recombination frequencies between the distant genes and intervening genes. Sturtevant and his colleagues were able to map the linear positions of genes in Drosophila into four groups, one for each chromosome. Fig. 15. 7

A linkage map provides an imperfect picture of a chromosome. Map units indicate relative distance and order, not precise locations of genes. The frequency of crossing over is not actually uniform over the length of a chromosome. Combined with other methods like chromosomal banding, geneticists can develop cytological maps. These indicated the positions of genes with respect to chromosomal features. More recent techniques show the absolute distances between gene loci in DNA nucleotides.

Human Karyotype

Human Karyotype

Identify gender and other possibilities.

http: //www. tokyo-med. ac. jp/genet/cki-e. htm

Determination of gender 2 kinds of gametes determines sex of offpring: heterogametic sex XX – homogametic female all ova X XY – heterogametic male ½ sperm X; ½ Y Sry-sex determining region on Y is responsible for triggering events that lead to testicular development Sry (pleiotropic) codes for protein that regulates other genes

This X-Y system of mammals is not the only chromosomal mechanism of determining sex. Other options include the X-0 system, the Z-W system, and the haplodiploid system. Fig. 15. 8

Sex linked Disorders in Humans Color blindness; male pattern baldness X Hairy ears Y Hemophilia X Duchenne muscular dystrophy X If X linked and male gets a mutant X, male expresses trait even if recessive-only one X: hemizygous-only one copy of gene present Father’s can’t pass on to sons; pass to all daughters

Barr body In females, most diploid cells have only one fully functional X chromosome Lyon hypothesis (Mary Lyon) each embryonic cell inactivates one X producing densely staining body: Barr body Barr bodies are highly methylated: XIST gene X Inactive Specific Transcript (RNA) Barr bodies are reactivated in gonadal cells that undergo meiosis to form gametes Females are mosaic- could be paternal or maternal X expressed (calico cats; sweat gland dev in humans)

Calico Cats

Calico Cat

Phenylketonuria Autosomal recessive Many have blue eyes and are lighter than other family members Inability to breakdown phenylalanine or its breakdown products (tyrosine) Mental retardation if not detected early Prominent cheek/jaw bones Microcephaly in untreated cases

Alterations of chromosome number Nondisjunction: meiotic or mitotic error during which certain homologous chromosomes or sister chromatids fail to separate Meiosis I: homologous pair does not separate Meiosis II: sister chromatids do not separate Results in one gamete receiving two of same type of chromosome and another gamete receiving no copy

Aneuploidy Aneuploic offspring may result if normal gamete unites w aberrant one produced as a result of nondisjunction Aneuploid cell has a chromosome in triplicate: trisomic Aneuploid with missing chromosome is monosomic When aneuploid zygote divides by mitosis, every cell has chromosomal anomaly

Down’s Syndrome Karyotype

Down’s Syndrome Age 35 1/380 Age 45 1/30 Sm head/flat back Thick tongues Extra skin on neck Slant eye/ epicanthal folds Flat nose bridge Short fingers/ single crease Wide space btwn 1 st and 2 nd toe Vary degrees MR Heart malformed Digestive tract problems

“somy” vs “ploidy” “somy” a chromosome or gene or piece of a chromosome is altered in number “ploidy” an entire set of chromosomes is added or missing Triploidy: 3 n; tetraploidy: 4 n Triploid: fertilization of an abnormal diploid egg produced by total nondisjunction Tetraploid: diploid zygote mitosis w no cytokinesis Important in plant evolution; rare among animals (may occur in patches)

Sex chromosome aneuploidies Less severe than autosomal aneuploidies May be due to the Y carrying few genes and copies of the X becoming Barr bodies XO Turner’s girls; XXX superfemale or triple X syndrome XXY Klinefelter’s syndrome XYY Extra Y syndrome; normal male, taller than family

Turner’s Girls XO Short stature, short web neck No ovarian function Short fingers/toes Irregular rotation wrist and elbow joints Heart problems Kidney problems Osteoporosis Problems w social interactions Problems w nonverbal problem solving Problems spatial/visuallike driving

Klinefelter’s Syndrome XXY Breast development/ sparse body hair Sm testes Taller than family Tend to be overweight Language dev problem

Alterations of chromosome structure Deletion: lose fragment lacking a centromere Fragment joins to homologous chromosome: duplication Joins to nonhomologous chromosome: translocation Reattach to original chromosome in reverse order: inversion Occurs in unequal or nonreciprocal crossovers (position effects alter phenotype)

Cri du Chat Karyotype

Cri du Chat Deletion #5 short arm • High-pitched cry (identified as a cat-like cry) • Low birth weight • Poor muscle tone (hypotonia) • Microcephaly (small head size) • Micrognathis (small jaw) • Hypertelorism (wide spaced eyes) • Round face • Epicanthal folds • Low set ears • Feeding difficulties • Delays in walking • Hyperactivity • Scoliosis • Language difficulties • Mental retardation • Organ defects

Patau syndrome 1/10, 000 live births Microcephaly Sm eyes, absent eye, retina faulty Cleft lip/palate Ear, finger, toe and other abnormalities Heart defects/heart on right side

Patau Syndrome (multiple defects)

William’s Syndrome Elphin features-wide mouth, slack lower lip, full cheeks, wide spaced teeth Microdelection of #7 Highly verbal Obsession on some objects-wheels, cars, hoovers… Hypersensitivity to noise Low attention span gregarious

CML: Chronic Myelogenous Leukemia Philadelphia chromosome: translocation of a piece of chromosome 22 with a small fragment from chromosome 9 Chronic phase may last decades, few symptoms Accelerated phase: enlarged spleen, fever, bone pain Blast crisis: >>#immature white blood cellsleukemia Risk from infection and treatment

Genomic imprinting Expression of some traits depend on which parent contributes the alleles for those traits

Angelman Syndrome head flat/microcephaly Tongue thrusting Swallowing disorders Wide mouth; wide spaced teeth Light hair & eyes compared to family Strabismus Sleep disorders Fascination w water Seizures Dev delay; functionally severe Speech problems/ nonverbal Motor problems Deletion of gene on maternal #15 gene or 2 copies of normal #15 from dad

Prader-Willi Syndrome Poor muscle tone Chronic hunger MR Problem behaviors Short stature Light hair/eyes compared to family Deletion #15 paternal Or 2 copies normal #15 maternal

Triplet repeats Sections of DNA where specific triplet of nucleotides is repeated many times Occur normally in many places in human genome Progressive addition of triplet repeats can lead to genetic disorders such as Fragile X syndrome and Huntington’s disease

Fragile X Occurs in males and females Most common genetic cause of mental retardation Triplet repeat, CGG, is repeated up to 50 x on one tip of a normal X chromosome, but on a fragile X chromosome is repeated >200 x Occurs incrementally over generations; repeats accrue from one generation to the next (prefragile X to fragile X) More likely to occur if X inherited from mother

Huntington’s disease Locus is near tip of #4, has a CAG extended triplet repeat Triplet repeat at the locus is more likely to extend if allele is inherited from father rather than from mother

Extranuclear Genes Occur in cytoplasmic organelles such as plastids and mitochondria Are not inherited in Mendelian fashion In plants, maternal plastid genes control variegation of leaves Mitochondria are exclusively from maternal cytoplasm (some metabolic diseases transmitted this way)