2Sex linked traits 1910 | 1933 Genes are on sex chromosomes as opposed to autosomal chromosomesfirst discovered by T.H. Morgan at Columbia U.Drosophila breedinggood genetic subjectprolific2 week generations4 pairs of chromosomesXX=female, XY=male
3Classes of chromosomes autosomal chromosomessex chromosomes
4Discovery of sex linkage true-breedingred-eye femaletrue-breedingwhite-eye maleXP100%red eye offspringF1generation(hybrids)100%red-eye female50% red-eye male50% white eye maleF2generation
5What’s up with Morgan’s flies? xxRRrrRrRrrrRrRRrRrRRRRrRRrRrrRrrr100% red eyes3 red : 1 white
6Genetics of Sex X Y X XX XY X XX XY In humans & other mammals, there are 2 sex chromosomes: X & Y2 X chromosomesdevelop as a female: XXgene redundancy, like autosomal chromosomesan X & Y chromosomedevelop as a male: XYno redundancyXYXXXXYXXXXY50% female : 50% male
7Let’s reconsider Morgan’s flies… xxXRXRXrYXRXrXRYXrYXRYXRXRXRXrXRYXRXRXRYXRXrXRXrXRYXRXrXrY100% red females50% red males; 50% white males100% red eyes
8Genes on sex chromosomes Y chromosomefew genes other than SRYsex-determining regionmaster regulator for malenessturns on genes for production of male hormonesmany effects = pleiotropy!X chromosomeother genes/traits beyond sex determinationmutations:hemophiliaDuchenne muscular dystrophycolor-blindnessDuchenne muscular dystrophy affects one in 3,500 males born in the United States.Affected individuals rarely live past their early 20s.This disorder is due to the absence of an X-linked gene for a key muscle protein, called dystrophin.The disease is characterized by a progressive weakening of the muscles and loss of coordination.
9Human X chromosome Sex-linked usually means “X-linked” Duchenne muscular dystrophyBecker muscular dystrophyIchthyosis, X-linkedPlacental steroid sulfatase deficiencyKallmann syndromeChondrodysplasia punctata,X-linked recessiveHypophosphatemiaAicardi syndromeHypomagnesemia, X-linkedOcular albinismRetinoschisisAdrenal hypoplasiaGlycerol kinase deficiencyIncontinentia pigmentiWiskott-Aldrich syndromeMenkes syndromeCharcot-Marie-Tooth neuropathyChoroideremiaCleft palate, X-linkedSpastic paraplegia, X-linked,uncomplicatedDeafness with stapes fixationPRPS-related goutLowe syndromeLesch-Nyhan syndromeHPRT-related goutHunter syndromeHemophilia BHemophilia AG6PD deficiency: favismDrug-sensitive anemiaChronic hemolytic anemiaManic-depressive illness, X-linkedColorblindness, (several forms)Dyskeratosis congenitaTKCR syndromeAdrenoleukodystrophyAdrenomyeloneuropathyEmery-Dreifuss muscular dystrophyDiabetes insipidus, renalMyotubular myopathy, X-linkedAndrogen insensitivityChronic granulomatous diseaseRetinitis pigmentosa-3Norrie diseaseRetinitis pigmentosa-2Sideroblastic anemiaAarskog-Scott syndromePGK deficiency hemolytic anemiaAnhidrotic ectodermal dysplasiaAgammaglobulinemiaKennedy diseasePelizaeus-Merzbacher diseaseAlport syndromeFabry diseaseAlbinism-deafness syndromeFragile-X syndromeImmunodeficiency, X-linked,with hyper IgMLymphoproliferative syndromeOrnithine transcarbamylasedeficiencyHuman X chromosomeSex-linkedusually means “X-linked”more than 60 diseases traced to genes on X chromosome
10Map of Human Y chromosome? < 30 genes on Y chromosomeSex-determining Region Y (SRY)linkedChannel Flipping (FLP)Catching & Throwing (BLZ-1)Self confidence (BLZ-2) note: not linked to ability geneDevotion to sports (BUD-E)Addiction to death & destruction movies (SAW-2)Scratching (ITCH-E)Spitting (P2E)Inability to express affection over phone (ME-2)Selective hearing loss (HUH)Total lack of recall for dates (OOPS)Air guitar (RIF)
11Hemophilia is a sex-linked recessive trait defined by the absence of one or more clotting factors. These proteins normally slow and then stop bleeding.Individuals with hemophilia have prolonged bleeding because a firm clot forms slowly.Bleeding in muscles and joints can be painful and lead to serious damage.Individuals can be treated with intravenous injections of the missing protein.
12Hemophilia XHXh XHY Hh x HH XH XHXh XH Y Xh XHXH XHXH XHY XHY XH Xh XH sex-linked recessiveHemophiliaXHXhXHYHh x HHXHXHXhXHYmale / spermXhXHXHXHXHXHYXHYXHXhfemale / eggsXHXHYXHXhXHXhXhYXhYYcarrierdisease
13X-inactivation Female mammals inherit 2 X chromosomes XH XHXh Xh one X becomes inactivated during embryonic developmentcondenses into compact object = Barr bodywhich X becomes Barr body is randompatchwork trait = “mosaic”patches of blackXHXHXhXhtricolor cats can only be femalepatches of orange
14Male pattern baldness Sex influenced trait autosomal trait influenced by sex hormonesage effect as well = onset after 30 years olddominant in males & recessive in femalesB_ = bald in males; bb = bald in females
15Environmental effects Phenotype is controlled by both environment & genesHuman skin color is influenced by both genetics & environmental conditionsCoat color in arctic fox influenced by heat sensitive allelesThe relative importance of genes & the environment in influencing human characteristics is a very old & hotly contested debatea single tree has leaves that vary in size, shape & color, depending on exposure to wind & sunfor humans, nutrition influences height, exercise alters build, sun-tanning darkens the skin, and experience improves performance on intelligence testseven identical twins — genetic equals — accumulate phenotypic differences as a result of their unique experiencesColor of Hydrangea flowers is influenced by soil pH
16Changes in chromosome structure deletionloss of a chromosomal segmentduplicationrepeat a segmentinversionreverses a segmenttranslocationmove segment from one chromosome to anothererror of replicationerror of crossing over
17Chromosomal abnormalities Incorrect number of chromosomesnondisjunctionchromosomes don’t separate properly during meiosisbreakage of chromosomesdeletionduplicationinversiontranslocation
18NondisjunctionProblems with meiotic spindle cause errors in daughter cellshomologous chromosomes do not separate properly during Meiosis 1sister chromatids fail to separate during Meiosis 2too many or too few chromosomes2nn-1nn+1
19Alteration of chromosome number error in Meiosis 1error in Meiosis 2all with incorrect number1/2 with incorrect number
20Nondisjunction Baby has wrong chromosome number trisomy monosomy cells have 3 copies of a chromosomemonosomycells have only 1 copy of a chromosomen+1nn-1ntrisomy2n+1monosomy2n-1
21Human chromosome disorders High frequency in humansmost embryos are spontaneously abortedalterations are too disastrousdevelopmental problems result from biochemical imbalanceimbalance in regulatory molecules?hormones?transcription factors?Certain conditions are toleratedupset the balance less = survivablebut characteristic set of symptoms = syndrome
22Down syndromeTrisomy 213 copies of chromosome 211 in 700 children born in U.S.Chromosome 21 is the smallest human chromosomebut still severe effectsFrequency of Down syndrome correlates with the age of the motherTrisomy 13 occurs in about 1 out of every 5,000 live births. It is a syndrome with multiple abnormalities, many of which are not compatible with life. More than 80% of children with trisomy 13 die in the first month. Trisomy 13 is associated with multiple abnormalities, including defects of the brain that lead to seizures, apnea, deafness, and eye abnormalities. The eyes are small with defects in the iris (coloboma ). Most infants have a cleft lip and cleft palate, and low-set ears. Congenital heart disease is present in approximately 80% of affected infants. Hernias and genital abnormalities are common.Trisomy 18 is a relatively common syndrome affecting approximately 1 out of 3,000 live births, and affecting girls more than three times as often as boys. The presence of an extra number 18 chromosome leads to multiple abnormalities. Many of these abnormalities make it hard for infants to live longer than a few months.The cri du chat syndrome is caused by the deletion of information on chromosome 5. It is likely that multiple genes on chromosome 5 are deleted. One deleted gene, called TERT (telomerase reverse transcriptase) is involved in control of cell growth, and may play a role in how some of the features of cri cu chat develop. The cause of this rare chromosomal deletion is not known, but it is expected that the majority of cases are due to spontaneous loss of a piece of chromosome 5 during development of an egg or sperm. A minority of cases result from one parent carrying a rearrangement of chromosome 5 called a translocation. Between 1 in 20,000 and 1 in 50,000 babies are affected. This disease may account for up to 1% of individuals with severe mental retardation. Infants with cri du chat syndrome commonly have a distinctive cat-like cry. They also have an extensive grouping of abnormalities, with severe mental retardation being the most important.
23Down syndrome & age of mother Mother’s ageIncidence of Down SyndromeUnder 30<1 in 1000301 in 900351 in 400361 in 300371 in 230381 in 180391 in 135401 in 105421 in 60441 in 35461 in 20481 in 16491 in 12Rate of miscarriage due to amniocentesis:1970s data 0.5%, or 1 in 200 pregnancies2006 data <0.1%, or 1 in 1600 pregnancies
24Genetic testing Amniocentesis in 2nd trimester Analysis of karyotype sample of embryo cellsstain & photograph chromosomesAnalysis of karyotype
25Sex chromosomes abnormalities Human development more tolerant of wrong numbers in sex chromosomeBut produces a variety of distinct syndromes in humansXXY = Klinefelter’s syndrome maleXXX = Trisomy X femaleXYY = Jacob’s syndrome maleXO = Turner syndrome female
26Klinefelter’s syndrome XXY maleone in every 2000 live birthshave male sex organs, but are sterilefeminine characteristicssome breast developmentlack of facial hairtallnormal intelligence
27Klinefelter’s syndrome How many Barr bodies would you expect?
28Jacob’s syndrome male XYY Males 1 in 1000 live male births extra Y chromosomeslightly taller than averagemore activenormal intelligence, slight learning disabilitiesdelayed emotional maturitynormal sexual development
29Trisomy X XXX 1 in every 2000 live births produces healthy females Why?Barr bodiesall but one X chromosome is inactivatedHow many Barr bodies would you expect?
30Turner syndrome Monosomy X or X0 1 in every 5000 births varied degree of effectswebbed neckshort staturesterileHow many Barr bodies would you expect?