beyond Mendel - the chromosomal basis of inheritance

1. beyond Mendel - the chromosomal basis of inheritance biology 1

2. Mendel’s Laws based on chromosomal behavior • Specific advances in the knowledge of genetics • Sex-linkage • Recombination • Linked genes • Sex-linked disorders • Alterations of chromosome number/structure

3. A chromosome basis for Mendel • Observed by late 1900s; • Chromosomes and genes are both paired in diploid cells • Homologous chromosomes separate and allele pairs segregate during meiosis • Fertilization restores the paired condition for both chromosomes and genes • This led to the chromosome theory of inheritance • Mendelian factors or genes are located in chromosomes • It is the chromosomes that segregate and independently assort

4. Thomas Morgan substantiated this theory with work on fruit flies, Drosophila (2n = 8) • Adopted a new method of symbolizing genes and alleles • A gene’s symbol is based on the first mutant, non-wild type discovered (e.g. w = white eye allele in Drosophila) • If the mutant is dominant, the first letter is capitalized (e.g. Cy = curly wings in Drosophila) • Wild type (normal) gets superscript + (e.g. Cy+ is the allele for normal, straight wings)

5. Sex-linkage • Morgan crossed a white-eyed male (w) with a red-eyed female (w+w+) • In the F1, all progeny had red eyes, implying that red-eye was dominant • In the F2, white-eye trait was only found in males - females were always red-eye • Deduction: the gene for eye color is on the X chromosome, since • If eye color is located only on the x-chromosome, then females carry to copies of the gene (XX), while males (XY) only carry one • Since the mutant allele is recessive, wa white eyed female must have that allele on both X chromosomes, which would be impossible for F2 females • A white-eyed male has no wild type to mask the recessive mutant allele, so a single copy of the mutant allele confers white eyes

6. Linked genes • Linked genes are located in the same chromosome and tend to be inherited together (ie, do not sort independently, 9:3:3:1 ratio is not preserved) • For example, in a non-linked dihybrid test-cross, e.g. YyRr x yyrr Yellow round Green wrinkled F1 YyRr yyrr yyRr Yyrr Yellow round green wrinkled green round yellow wrinkled 1 : 1 : 1 : 1 (Parental types) (Recombinant types)

7. If genes are totally linked, some possible phenotypes should not appear (although sometimes they can, if linakge is not complete) • For example, Morgan crossed black body (b), normal wings (vg+) vs. wild type body (b+), vestigial wings (vg) • Conclusion: the two genes are neither completely linked or unlinked Recombination frequency = 391 recomb./2300 offspring = 17%

8. 17 9.0 9.5 b cn vg • If genes are completely linked, then expect only parental types in offspring • Crossing over in Prophase I accounts for recombination of linked genes • Genes that are located in the same chromosome close to each other are less likely to separate during synapsis. Genes that are further apart are more likely to be separated • If crossing-over occurs randomly, percentage of crossing-over can be used to map location of genes on a chromosome • When linked genes are further apart than 50 cM, they are indistinguishable to non-linked genes • Cytological mapping can now pinpoint precise location on chromosome

9. Sex-linked disorders • Since the x-chromosome is larger, there are more x-linked traits: most have no homologous loci on the y-chromosome • Most genes on the y-chromosome have no x-counterparts, and encode traits only found in males • Examples of sex-linked traits include color blindness and hemophilia. • Fathers pass X-linked alleles to only, and all of their daughters. Fathers cannot pass x-sex-linked traits to sons • Mothers can pass X-linked alleles to both sons and daughters • X-sex-linked traits are rarer in females since they tend to be recessive, and thus require a homozygous condition • Any male that receives an X-sex-linked chromosome, recessive or not, will express it, since they are hemizygous • As a consequence, males tend to display more sex-linked disorders.

10. X-inactivation • To prevent females from receiving a double-dose of sex-linked traits, one X-chromosome is typically inactivated, contracting into a dense object called a barr body • Barr bodies are reactivated in gonadal cells for meiosis • Choice of which X to inactivate (maternal or paternal inherited) is randomly selected in embryonic cells • Thus heterozygous females display sex-linked traits on a 50/50 basis (e.g., calico cats) • Formation of barr body appears to be by methylation of cytosine

11. Alteration of chromosome number • Meiotic nondisjunction: a homologous pair does not separate in Metaphase I, or chromatids do not separate in Metaphase II • Mitotic nondisjunction: occurs at metaphase. If early in embryonic development, can be passed onto a large number of cells • Aneuploidy - an abnormal number of chromosomes (trisomic or monosomic); for example, Down syndrome is trisomy of chromosome 21 • Polyploidy - a chromosome number that is more than two complete chromosome sets; this is very common in plants

12. Alteration of chromosome structure • Fragments breaking off from chromosomes may result in deletions • Addition of those fragments to: • Homologous chromosomes causes a replication • Nonhomologous chromosomes causes a translocation • Original chromosome in reverse order causes an inversion • Crossovers are usually reciprocal, but sometimes a chromatid gives up more genes than it receives in an unequal crossover (creates one deletion and one duplication)

13. Human disorders resulting from chromosomal alteration • Down syndrome effects 1/700. The result of trisomy on chromosome 21 (an autosome), causes specific facial features, heart defects, retardation, and proneness to leukemia • Sex chromosome aneuploidies are typically less severe because • The Y chromosome carries less genes • Copies of the X-chromosome may be inactivated as barr bodies