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The Chromosomal Basis of Inheritance – Beyond Mendelian Genetics Beyond Mendelian Ideas • Mendel’s “hereditary factors” were genes • Genes are located on chromosomes at specific loci • The location of a particular gene can be seen by tagging isolated chromosomes with a fluorescent dye that highlights the gene Mendelian Inheritance • The chromosome theory of inheritance states: – Mendelian genes have specific loci (positions) on chromosomes – Chromosomes undergo segregation and independent assortment • The behavior of chromosomes during meiosis accounts for Mendel’s laws of segregation and independent assortment P Generation Yellow-round seeds (YYRR) Y Y R r R Green-wrinkled seeds ( yyrr) y y r Meiosis Fertilization y R Y Gametes r All F1 plants produce yellow-round seeds (YyRr) F1 Generation R R y r Y Y LAW OF SEGREGATION The two alleles for each gene separate during gamete formation. y r LAW OF INDEPENDENT ASSORTMENT Alleles of genes on nonhomologous chromosomes assort independently during gamete formation. Meiosis R r Y y r R Y y Metaphase I 1 1 R r Y y r R Y y Anaphase I R r Y y Metaphase II r R Y y 2 2 Y Y Gametes R R 1/ F2 Generation 4 YR y r r r 1/ 4 Y Y y r 1/ yr 4 Yr y y R R 1/ 4 yR An F1 F1 cross-fertilization 3 3 9 :3 :3 :1 Morgan’s Experiments • The first solid evidence associating a specific gene with a specific chromosome came from Thomas Hunt Morgan, an embryologist • Morgan’s experiments with fruit flies provided convincing evidence that chromosomes are the location of Mendel’s heritable factors • Several characteristics make fruit flies a convenient organism for genetic studies: – They breed at a high rate – A generation can be bred every two weeks – They have only four pairs of chromosomes • Morgan noted wild type, or normal, phenotypes that were common in the fly populations • Traits alternative to the wild type are called mutant phenotypes Discovery of sex linkage P F1 true-breeding red-eye female X true-breeding white-eye male Huh! Sex matters?! 100% red eye offspring generation (hybrids) F2 generation 100% red-eye female 50% red-eye male 50% white eye male Morgan mated white eyed male (mutant) with red eyed female (wild type) Result all F1 had red eyes An F2 cross produced a 3:1 red:white eye ratio, but only males had white eyes EXPERIMENT P Generation F1 Generation All offspring had red eyes RESULTS F2 Generation Morgan determined the white-eyed mutant allele is located on the X chromosome CONCLUSION P Generation w+ X X w+ X Y w Eggs F1 Generation w+ Sperm w+ w+ w w+ Eggs F2 Generation w w+ w Sperm w+ w+ w+ w w w+ Morgan’s finding supported the chromosome theory of inheritance What’s up with Morgan’s flies? x F 1 RR r x rr Rr r R Rr Rr R Rr Rr 100% red eyes Rr R Doesn’t work that way! F 2 r R RR Rr r Rr rr 3 red : 1 white Sex-linked genes • Chromosomal basis of sex determination: • Humans – XY • The SRY gene on the Y chromosome codes for the development of testes • Females – XX • males are XY • Each ovum contains an X • Sperm contains either an X or a Y Genetics of Sex • In humans & other mammals, there are 2 sex chromosomes: X & Y – 2 X chromosomes • develop as a female: XX gene redundancy, like autosomal chromosomes – an X & Y chromosome X Y X XX XY X XX XY • develop as a male: XY • no redundancy 50% female : 50% male Sex Chromosomes - Humans 44 + XY 44 + XX Parents 22 + 22 + or Y X Sperm 44 + XX 22 + X + Egg or 44 + XY Zygotes (offspring) (a) The X-Y system Sex Chromosomes - Grasshoppers 22 + XX (b) The X-0 system 22 + X Sex Chromosomes - Birds 76 + ZW (c) The Z-W system 76 + ZZ Sex Chromosomes – Bees 32 (Diploid) (d) The haplo-diploid system 16 (Haploid) Let’s reconsider Morgan’s flies… x XR XR Xr XR XR XR X r XR X r x X rY XR Xr Y XRY XRY 100% red eyes XR BINGO! Xr XRY XR Y XR XR XRY X R Xr X rY 100% red females 50% red males; 50% white males Inheritance of Sex-Linked Genes • A gene located on either sex chromosome is a sex-linked gene • Sex-linked genes follow specific patterns of inheritance, for a recessive sex-linked trait to be expressed – A female needs two copies of the allele – A male needs only one copy of the allele (he only gets one X chromosome) • Sex-linked recessive disorders are much more common in males than in females because they are found on the X chromosome Human X chromosome • Sex-linked – usually means “X-linked” Duchenne muscular dystrophy Becker muscular dystrophy Chronic granulomatous disease Retinitis pigmentosa-3 Norrie disease Retinitis pigmentosa-2 Ichthyosis, X-linked Placental steroid sulfatase deficiency Kallmann syndrome Chondrodysplasia punctata, X-linked recessive Hypophosphatemia Aicardi syndrome Hypomagnesemia, X-linked Ocular albinism Retinoschisis Adrenal hypoplasia Glycerol kinase deficiency Ornithine transcarbamylase deficiency Incontinentia pigmenti Wiskott-Aldrich syndrome Menkes syndrome – more than 60 diseases Anhidrotic ectodermal dysplasia Agammaglobulinemia traced to genes Kennedy disease Pelizaeus-Merzbacher disease on X Alport syndrome Fabry disease chromosome Immunodeficiency, X-linked, Sideroblastic anemia Aarskog-Scott syndrome PGK deficiency hemolytic anemia with hyper IgM Lymphoproliferative syndrome Albinism-deafness syndrome Fragile-X syndrome Androgen insensitivity Charcot-Marie-Tooth neuropathy Choroideremia Cleft palate, X-linked Spastic paraplegia, X-linked, uncomplicated Deafness with stapes fixation PRPS-related gout Lowe syndrome Lesch-Nyhan syndrome HPRT-related gout Hunter syndrome Hemophilia B Hemophilia A G6PD deficiency: favism Drug-sensitive anemia Chronic hemolytic anemia Manic-depressive illness, X-linked Colorblindness, (several forms) Dyskeratosis congenita TKCR syndrome Adrenoleukodystrophy Adrenomyeloneuropathy Emery-Dreifuss muscular dystrophy Diabetes insipidus, renal Myotubular myopathy, X-linked Map of Human Y chromosome? < 30 genes on Y chromosome Sex-determining Region Y (SRY) Channel Flipping (FLP) Catching & Throwing (BLZ-1) Self confidence (BLZ-2) Devotion to sports (BUD-E) Addiction to death & destruction movies (SAW-2) note: not linked to ability gene Air guitar (RIF) Scratching (ITCH-E) Spitting (P2E) Inability to express affection over phone (ME-2) linked Selective hearing loss (HUH) Total lack of recall for dates (OOPS) Transmission of an X-linked recessive disorder XNXN Sperm Xn Xn Y (a) Sperm XN Y Eggs XN XNXn XNY XN XNXn XNY Xn (b) Sperm Xn Y Eggs XN XNXN XNY XNXn XNY XNXn Xn Y Y Eggs XN XNXn XNY Xn XN Xn Y Xn Xn Xn Xn Y (c) X linked disorders: Color blindness, Duchenne muscular dystrophy and Hemophilia Hemophilia sex-linked recessive H Xh HY XHh x XHH XH female / eggs male / sperm XH XH Y XH XH XHY XH Xh Xh XH Xh XH Xh carrier XhY disease XHY Y Other Sex-Linked Disorders Duchene Muscular Dystrophy Color Blindness X Inactivation in Female Mammals • In mammalian females, one of the two X chromosomes in each cell is randomly inactivated during embryonic development • The inactive X condenses into a Barr body • If a female is heterozygous for a particular gene located on the X chromosome, she will be a mosaic for that character X-inactivation • Female mammals inherit 2 X chromosomes – one X becomes inactivated during embryonic development • condenses into compact object = Barr body • which X becomes Barr body is random – patchwork trait = “mosaic” patches of black XH XH Xh tricolor cats can only be female Xh patches of orange X chromosomes Early embryo: Two cell populations in adult cat: Active X Allele for orange fur Allele for black fur Cell division and X chromosome inactivation Active X Inactive X Black fur Orange fur Linked Genes • Linked genes tend to be inherited together because they are located near each other on the same chromosome • Genes located on the same chromosome that tend to be inherited together are called linked genes • Morgan did other experiments with fruit flies to see how linkage affects inheritance of two characters • Morgan crossed flies that differed in traits of body color and wing size b vg b+ vg+ Parents in testcross Most offspring b vg b vg b+ vg+ b vg or b vg b vg EXPERIMENT P Generation (homozygous) Wild type (gray body, normal wings) b+ b+ vg+ vg+ Double mutant (black body, vestigial wings) b b vg vg EXPERIMENT P Generation (homozygous) Wild type (gray body, normal wings) b b vg vg b+ b+ vg+ vg+ F1 dihybrid (wild type) b+ b vg+ vg Double mutant (black body, vestigial wings) TESTCROSS Double mutant b b vg vg EXPERIMENT P Generation (homozygous) Wild type (gray body, normal wings) Double mutant (black body, vestigial wings) b b vg vg b+ b+ vg+ vg+ F1 dihybrid (wild type) Double mutant TESTCROSS b+ b vg+ vg Testcross offspring b b vg vg b vg b+ vg b vg+ Wild type (gray-normal) Blackvestigial Grayvestigial Blacknormal b+ b vg+ vg b b vg vg b+ b vg vg b b vg+ vg Eggs b+ vg+ b vg Sperm EXPERIMENT P Generation (homozygous) Wild type (gray body, normal wings) Double mutant (black body, vestigial wings) b b vg vg b+ b+ vg+ vg+ F1 dihybrid (wild type) Double mutant TESTCROSS b+ b vg+ vg Testcross offspring b b vg vg b vg b+ vg b vg+ Wild type (gray-normal) Blackvestigial Grayvestigial Blacknormal b+ b vg+ vg b b vg vg b+ b vg vg b b vg+ vg Eggs b+ vg+ b vg Sperm PREDICTED RATIOS If genes are located on different chromosomes: 1 : 1 : 1 : 1 If genes are located on the same chromosome and parental alleles are always inherited together: 1 : 1 : 0 : 0 965 : 944 : 206 : 185 RESULTS Genetic Recombination and Linkage • Morgan found that body color and wing size are usually inherited together in specific combinations (parental phenotypes) • He noted that these genes do not assort independently, and reasoned that they were on the same chromosome • However, non-parental phenotypes (recombinant types) were also produced • Understanding this result involves exploring genetic recombination, the production of offspring with combinations of traits differing from either parent. (We did this in Meiosis!) • The genetic findings of Mendel and Morgan relate to the chromosomal basis of recombination Recombination of Unlinked Genes: Independent Assortment of Chromosomes Combinations of traits in some offspring differ from either parent Phenotype matching one of the parental phenotypes are parental types Gametes from greenwrinkled homozygous recessive parent ( yyrr) Gametes from yellow-round heterozygous parent (YyRr) YR yr Yr yR YyRr yyrr Yyrr yyRr yr Non-parental phenotypes (new combinations of traits) are recombinant types, or recombinants A 50% frequency of recombination is observed for any two genes on different chromosomes Parentaltype offspring Recombinant offspring Recombination of Linked Genes: Crossing Over • Morgan discovered that genes can be linked, but the linkage was incomplete, as evident from recombinant phenotypes • Morgan proposed that some process must sometimes break the physical connection between genes on the same chromosome • That mechanism was the crossing over of homologous chromosomes Gray body, normal wings (F1 dihybrid) Testcross parents Big Idea Here! The further apart genes are on a chromosome the less likely that that will be transferred together in a cross over event. Genes located very close to one another close to the end of the same choromosome or chromotid are often transferred together by default of their position. Replication of chromosomes Meiosis I Black body, vestigial wings (double mutant) b+ vg+ b vg b vg b vg Replication of chromosomes b+ vg+ b vg b+ vg+ b vg b vg b vg b vg b vg b+ vg+ Meiosis I and II b+ vg b vg+ b vg Meiosis II Recombinant chromosomes Eggs Testcross offspring b+ vg+ b vg b+ vg b vg+ 965 944 206 185 Wild type (gray-normal) Blackvestigial Grayvestigial Blacknormal b+ vg+ b vg b+ vg b vg+ b vg b vg b vg b vg Parental-type offspring Recombinant offspring 391 recombinants Recombination 100 = 17% = frequency 2,300 total offspring b vg Sperm Testcross parents Black body, vestigial wings (double mutant) Gray body, normal wings (F1 dihybrid) Replication of chromosomes Meiosis I b+ vg+ b vg b vg b vg b+ vg+ b vg b+ vg+ b vg b vg b vg b vg b vg b+ vg+ b+ Meiosis I and II vg b vg+ b vg Meiosis II Recombinant chromosomes Parental types b+ vg+ b vg Eggs b+ vg b vg+ b vg Sperm Replication of chromosomes Recombinant chromosomes Eggs Testcross offspring b+ vg+ b vg b+ vg b vg+ 944 Wild type Black(gray-normal) vestigial 206 Grayvestigial 185 Blacknormal 965 b+ vg+ b vg b+ vg b vg+ b vg b vg b vg b vg Parental-type offspring Recombinant offspring 391 recombinants Recombination 100 = 17% = frequency 2,300 total offspring b vg Sperm Mapping the Distance Between Genes Using Recombination Data • A genetic map, an ordered list of the genetic loci along a particular chromosome • The farther apart two genes are, the higher the probability that a crossover will occur between them and therefore the higher the recombination frequency • A linkage map is a genetic map of a chromosome based on recombination frequencies • Distances between genes can be expressed as map units; one map unit equals a 1% recombination frequency • Map units indicate relative distance and order, not precise locations of genes! Genes that are far apart on the same chromosome can have a recombination frequency near 50% Such genes are physically linked, but genetically unlinked, and behave as if found on different chromosomes Recombination frequencies 9% Chromosome 9.5% 17% b cn vg • Recombination frequencies were used to make linkage maps of fruit fly genes on a chromosome. • Using methods like chromosomal banding, geneticists can develop cytogenetic maps of chromosomes • Cytogenetic maps indicate the positions of genes with respect to chromosomal features – Genes will have the same order but may have different distances than a linkage map Remember! The linkage map is based on recombination frequencies, so more data, more accuracy. Also, crossing over is random, not guaranteed, or there wouldn’t be any parental types! Mutant phenotypes – Linkage Map Short aristae 0 Long aristae (appendages on head) Black body 48.5 Gray body Cinnabar Vestigial eyes wings 57.5 Red eyes 67.0 Normal wings Wild-type phenotypes Brown eyes 104.5 Red eyes Alterations of chromosome number or structure cause some genetic disorders • Gross changes to chromosome often lead to spontaneous abortions (miscarriages) or cause a variety of developmental disorders • Major damage to a chromosome • Extra or missing chromosomes – Monosomy (2n-1) – Trisomy (2n+1) • Remember the Karyotype – looking for missing, extra or damaged chromosomes? Alterations of Chromosome Number • Non-disjunction, pairs of homologous chromosomes fail to separate normally during meiosis I or II. • As a result, one gamete receives two of the same type of chromosome, and another gamete receives no copy. • Aneuploidy (having an abnormal chromosome #) results from the fertilization of gametes in which non-disjunction occurred • A monosomic zygote has only one copy of a particular chromosome (monosomy) • A trisomic zygote has three copies of a particular chromosome (trisomy) ←Monosomy X Trisomy XXY → Meiosis I Nondisjunction (a) Nondisjunction of homologous chromosomes in meiosis I (b) Nondisjunction of sister chromatids in meiosis II Meiosis I Nondisjunction Meiosis II Nondisjunction (a) Nondisjunction of homologous chromosomes in meiosis I (b) Nondisjunction of sister chromatids in meiosis II Meiosis I Nondisjunction Meiosis II Nondisjunction Gametes n+1 n+1 n–1 n–1 n+1 n–1 n Number of chromosomes (a) Nondisjunction of homologous chromosomes in meiosis I (b) Nondisjunction of sister chromatids in meiosis II n Polyploidy Polyploidy is a condition in which an organism has more than two complete sets of chromosomes – Triploidy (3n) is three sets of chromosomes – Tetraploidy (4n) is four sets of chromosomes Polyploidy is common in plants, but not animals Polyploids are more normal in appearance than I’m a tetraploid! aneuploids Alterations of Chromosome Structure • Breakage of a chromosome can lead to four types of changes in chromosome structure: – Deletion removes a chromosomal segment – Duplication repeats a segment – Inversion reverses a segment within a chromosome – Translocation moves a segment from one chromosome to another (a) (b) (c) (d) A B C D E F G H A B C D E F G H A B C D E F G H A B C D E F G H Deletion Duplication A B C E F G H A B C B C D E Inversion A D C B E R F G H M N O C D E Reciprocal translocation M N O P Q F G H A B P Q R F G H Human Disorders Due to Chromosomal Alterations • Down Syndrome (Trisomy 21) – ~ 1:700 births in the U.S – frequency of Down syndrome increases with the age of the mother. Aneuploidy of Sex Chromosomes • Nondisjunction of sex chromosomes produces a variety of aneuploid conditions • XXY (Klinefelter syndrome) – is the result of an extra X chromosome in a male. • Monosomy X (Turner syndrome) – X females, who are sterile – it is the only known viable monosomy in humans Disorders Caused by Structurally Altered Chromosomes • The syndrome cri du chat (“cry of the cat”), results from a specific deletion in chromosome 5 – A child born with this syndrome is mentally retarded and has a catlike cry; individuals usually die in infancy or early childhood • Certain cancers, including chronic myelogenous leukemia (CML), are caused by translocations of chromosomes Normal chromosome 9 Translocated chromosome 9 Reciprocal translocation Normal chromosome 22 Translocated chromosome 22 (Philadelphia chromosome) Genomic Imprinting • The phenotype depends on which parent donated the alleles for that trait. • This type of variation is called genomic imprinting • Silencing of certain genes that are methylated during gamete production (addition of –CH3) of DNA, remember this from functional groups. • Genomic imprinting is thought to affect only a small fraction of mammalian genes • Most imprinted genes are critical for embryonic development • http://learn.genetics.utah.edu/content/epigenetics/imprinting/ Paternal chromosome Normal Igf2 allele is expressed Maternal chromosome Normal Igf2 allele is not expressed (a) Homozygote Wild-type mouse (normal size) Mutant Igf2 allele inherited from mother Normal size mouse (wild type) Imprinted genes are silenced by methylation during the S-phase of meiosis. The imprinted genes are not expressed. Mutant Igf2 allele inherited from father Dwarf mouse (mutant) Normal Igf2 allele is expressed Mutant Igf2 allele is expressed Mutant Igf2 allele is not expressed Normal Igf2 allele is not expressed (b) Heterozygotes Exceptions to the standard chromosome theory • There are two normal exceptions to Mendelian genetics • One exception involves genes located in the nucleus (linked genes), and the other exception involves genes located outside the nucleus – extra nuclear genes Inheritance of Extra-Nuclear Genes • Extra-nuclear genes (or cytoplasmic genes) are genes found in organelles in the cytoplasm (mitochondria and chloroplasts!) • Extra-nuclear genes are inherited maternally because the zygote’s cytoplasm comes from the egg • Some defects in mitochondrial genes prevent cells from making enough ATP and result in diseases that affect the muscular and nervous systems – • For example, mitochondrial myopathy and Leber’s hereditary optic neuropathy The first evidence of extra-nuclear genes came from studies on the inheritance of yellow or white patches on leaves of an otherwise green plant Only the nucleus from the sperm enters the egg. So all cytoplasmic genes are from the egg, maternally inherited. REVIEW Sperm P generation D gametes C B A Egg E + c b a d F f The alleles of unlinked genes are either on separate chromosomes (such as d and e) or so far apart on the same chromosome (c and f) that they assort independently. This F1 cell has 2n = 6 chromosomes and is heterozygous for all six genes shown (AaBbCcDdEeFf). Red = maternal; blue = paternal. D Each chromosome has hundreds or thousands of genes. Four (A, B, C, F) are shown on this one. e C B A F e d E cb a f Genes on the same chromosome whose alleles are so close together that they do not assort independently (such as a, b, and c) are said to be linked.