beyond Mendel - the chromosomal basis of inheritance biology 1

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

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

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)

Sex-linkage Morgan crossed a white-eyed male (w) with a red-eyed female (w + w + ) –In the F 1, 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 F 2 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

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. YyRrxyyrr Yellow roundGreen wrinkled F 1 YyRryyrryyRrYyrr Yellow round green wrinkled green round yellow wrinkled 1 : 1 : 1 : 1 (Parental types) (Recombinant types)

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%

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 b vgcn

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.

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

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

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)

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