Linkage, Recombination, and Pedigree Analysis Review

These flashcards cover key concepts from the lecture on linkage, recombination, and pedigree analysis in genetics to aid in exam preparation.

Define genetic linkage.

The tendency of genes that are located close to each other on a chromosome to be inherited together.

What is a chiasma?

The point of contact between two paired chromosomes during meiosis where crossing over and exchange of genetic information occurs.

What is crossing-over?

Physical process of reciprocal exchange of chromosome segments at corresponding symmetrical breaking and rejoining of segments.

What is recombination?

The process by which segments of DNA are broken and recombined to produce new combinations of alleles.

Define coupling in genetics.

A phase where two wild type alleles are on one homologous chromosome and mutant alleles on the other.

What is repulsion in genetics?

A phase where each homologous chromosome has one wild-type allele and one mutant allele.

What is a test cross?

Heterozygous x Homozygous Recessive cross

What is a genetic map?

A representation of the relative positions of genes on a chromosome.

Define linkage analysis.

Tracking genetic conditions through generations in relation of transmission of traits or phenotypes

What is Mendel's first law?

Segregation - Individuals possess two alleles, and a parent passes only one allele to their offspring.

What is Mendel's second law?

Independent Assortment - Inheritance of one pair of alleles is independent of the inheritance of another pair.

Explain the Chromosome theory of inheritance?

Genes are located on chromosomes

Movement of chromosomes during meiosis explains how traits are passed on

1. Genes reside on chromosomes

2. Genes and chromosomes show parallel behavior

3. Genes are chromosomes occur in pairs

4. During meiosis genes segregate

When does recombination occur in meiosis?

Anaphase I

What is complete linkage?

When genes are located close to one another on the same chromosome and NO recombinants are produced.

Define incomplete linkage.

When genes are on the same chromosome but are far enough apart that some recombination occurs.

Explain the relationship between crossing over and distance between genes when linked genes segregate togehter

More crossing over when genes are farther apart and less crossing over when genes are closer together.

Name an important concept regarding recombination’s effect on linkage

Linked genes segregate together while recombination breaks this link between them

What does a test cross help us reveal with linkage?

The effects of linkage and which alleles are transmitted by the parent.

What is an offspring outcome you will 100% have occur in independent assortment

Parentals/non-recombinants

What is a parental gamete?

Non-recombinant progeny that resemble one of the parents in their allele combinations.

What is a non-parental gamete?

Recombinant progeny that have non-parental combinations of alleles resulting from genetic recombination.

Explain the When, Where, Why, How of Mitotic Recombination

When: Interphase

Where: Common fragile sites in the genome and more

Why: Repairing breaks

How: Different ones, mainly Homologous recombination

Why is recombination so important?

Allows for adaptations and variation.

Why is recombination not always important?

Asexual reproduction does not recombine, and the Y chromosome can’t recombine

Explain the dynamic between independent assortment and linkage

Complete linkage = no independent assortment

No linkage = Independent assortment

Why do we never get a >50% recombination rate?

You have 4 chromatids, 2 pairs creating chromosomes. During crossing over only 2 chromatids cross over and exchange information, so the other two do not recombine. If 2/4 (1/2) never recombine, then you can’t have a >50% chance of recombination.

Define Chromatid

One of the two identical halves of a chromosome

In a single crossover, the frequency of recombinant gametes is half the frequency of crossing over, why?

For every combination of 4 chromatids, there are 2 that actually cross for recombinants

(2 chromosomes, 4 chromatids, 2 crossing chromatids)

When does crossing over occur?

During prophase I of meiosis.

Explain recombination frequency in incompletely linked genes

The parental (non-recombinant) gametes will be at a higher frequency compared to the non-parentals (recombinants)

What is the relation of recombination frequency to physical distance on a chromosome?

The greater the distance, the higher the recombination frequency.

Describe the expected offspring ratio for independent assortment.

1:1:1:1 ratio, 50% non-recombinants, 50% recombinants

What is the offspring ratio for

40, 40, 10, 10

Differences between Coupling and Repulsion other than formation

Coupling: See more parentals than non-parentals (in 40, 40, 10, 10, 40’s are parentals)

Repulsion: See more non-parentals than parentals (in 40, 40, 10, 10, 40’s are non-parentals)

Give the Testcross progeny and % progeny for Independent Assortment

AaBb - NR, 25%

aabb - NR, 25%

Aabb - R, 25%

aaBb - R, 25%

Give the Testcross progeny and % progeny for complete linkage (coupling).

AaBb - NR, 50%

aabb - NR, 50%

Give the Testcross progeny and % progeny for linkage with cross over (coupling)

AaBb - NR

Aabb - NR (NR’s >50%)

Aabb - R

aaBb - R (R’s <50%)

How many phenotypes do you get in a testcross with each of these: Independent Assortment, Complete Linkage, Linkage w/ Cross over

Independent Assortment: 4

Complete Linkage: 2

Linkage w/ Cross Over: 4

What influences genetic drift?

Random mating patterns and population size.

What do you do when results aren’t clear independent assortment or linkage. Example:

54 AaBb

56 aabb

42 Aabb

48 aaBb

Complete a Chi-Square test of independence. The null will always be independent assortment.

What is the formula for a chi-square test

Σ (O - E)² / E

How do you determine expected values?

Make a contingency table and then calculate: (row total \times column total) / grand total.

What is the purpose of a chi-square test of independence in genetics?

Determining whether the segregation of alleles at one locus is independent of the segregation of alleles at another locus without making any assumption about the probability of single-locus genetics

What alpha value determines rejection or failure to reject?

<0.05

Who proposed Recombination?

Thomas Morgan

Which student of Morgan’s determined that you can use distance to order alleles along a chromosome using recombination %?

Alfred Sturtevant

Define Non-allelic

Genes that are distinct from one another are located at different positions on a chromosome and do not influence each other's inheritance. They can segregate independently during meiosis.

What are the 6 steps to constructing a genetic map?

1. Design crosses involving traits of interest

2. Observe progeny ratios

3. Determine if they are linked (chi-squared)

4. Determine recombination frequencies

5. Determine linkage arrangement (Coupling or repulsion)

6. Position genes on chromosomes based on the data

How can you tell the recombinants from nonrecombinants in progeny?

Looking at the progeny numbers, when genes are linked the parentals are always the most frequent while recombinants are the least frequent

Progeny Numbers: 63, 28, 33, 77 Which are the recombinants? Why?

28 and 33 because they are the least compared to 63 and 77, which would be the parentals

What is the outcome of a double cross over?

Incomplete linkage

What do phenotypes of a double cross over look like?

Parentals because you basically didn’t switch positions (went from A, a to a, A, back to A, a) It mimics complete linkage

What do you need to know in order to predict the % of recombinant genotypes/phenotypes knowing the distance between two linked alleles?

1. What are the alleles?

2. Is there linkage?

3. What phase of linkage?

4. Distance between alleles

Steps of determining % of recombinants based on distance between two linked alleles?

1. Determine genotypes of parental and recombinant gametes noting orientation

2. Genotypic frequencies of each

3. Estimate frequencies of offspring from testcross

Steps for using a two-point test cross to determine map distances given only phenotypes

1. Write parental and F1 genotypes

2. Determine phase of linkage

3. Table up data

4. Determine Recombinants and their %

5. Map the genes

What is the difference between autosomal dominant and autosomal recessive inheritance?

Autosomal dominant traits appear in every generation, while recessive traits can skip generations.

In 3 point test crosses, how many progeny types can be output?

2³ aka 8

Ordering the top chromosome first, list all 8 possibilities of a 3-point test cross

1. ABC

2. abc

3. AbC

4. aBc

5. Abc

6. aBC

7. abC

8. ABc

What characterizes X-linked recessive inheritance?

More males affected, mothers may be carriers, does not pass from father to son.

How can you tell double cross overs when given out of order progeny numbers/genotypes?

Lowest progeny #’s will always be double cross overs

Of these numbers of progeny, which ones would be the double cross overs?

283, 287, 50, 52, 5, 3, 43, 41

5 and 3

What is the first step of ordering a 3-point test cross when you don’t know the parentals, or how the genes are ordered?

Try to find the middle gene correctly. The other two are easy after that

5 Steps to genetic linkage mapping

1. Find sets of related parents

2. Assemble patients into pedigrees

3. Genotype patients and other family members

4. Find genotypes that are inherited with the genes

5. Identify the region they are located by creating pedigree

What is a pedigree?

A pictorial diagram of family history that outlines the inheritance of traits.

What are discovery uses of Linkage Disequilibrium

We can see what cells are using a gene and what gene is causing a trait.

What is Linkage disequilibrium influenced by?

Selection, Recombination, Genetic drift, Mating, Population structure

Define linkage disequilibrium.

The non-random association of alleles at different loci.

What is GWAS?

Nonrandom association between a trait and alleles at many loci throughout the gene

Define Haplotype

Specific set of linked alleles along a chromosome

Linkage disequilibrium

Nonrandom association between alleles at two or more loci in a general population

Single Nucleotide Polymorphism (SNP)

Positions in the genome where a single nucleotide varies across individuals

The 3 GWAS Process Steps

1. Goal: Identify genomic regions associate with a phenotype

2. Fit statistical model at each SNP in genome

3. Use fitted models to test null hypothesis: No association with SNP and phenotype

Describe the 3 features of a Haplotype

1. Pattern of sequential SNP’s found on single chromosome

2. Block-wise structure separated by recombination spot

3. Within each block, recombination is rare due to tight linkage and only few haplotypes occur

Give an Example of a Haplotype

ATGTC

What are the haplotypes? (Only need to label the 3 SNPs)

1. GTA

2. AGT

3. AGA

What is the Logarithm of odds aka LOD score?

Estimation of the probabilities of obtaining the observed results under the assumption of linked genes with defines recombination or independent assortment.

What LOD score would give evidence of linkage?

3 or higher

How does recombination affect linkage analysis?

Recombination can eliminate linkage between mutated genes over generations.

Define monogenic traits.

Traits influenced by a single gene.

Define polygenic traits

Traits influenced by multiple genes.

What can cause deviations from expected offspring ratios in crosses?

Chance deviations, linkage, and recombination events.

What does the frequency of recombination indicate?

The distance between two genes on a chromosome.

How to calculate the frequency of recombination?

The # of recombinants/total progeny x 100

What is genetic mapping?

Determining the relative positions of non-allelic genes on chromosomes of a species using genetic crosses to locate genes on chromosomes relative to each other.

Observing progeny, calculating recombination, developing a linkage map

Define consanguineous

People descending from the same ancestor. Identity by descent so consanguineous mating results in increased chances of inheriting genetic disorders.

5 Rules for Autosomal Dominant Inheritance

1. Usually appears in both sexes, equal frequency

2. Both sexes transmit to offspring

3. Affected individuals typically have an affected parent

4. If 1 parent is heterozygous, and other is unaffected, ½ of offspring will be affected

   1. Unaffected parents don’t transmit the trait

5 Rules for Autosomal Recessive Inheritance

1. Appears in both sexes with equal frequency

2. Tends to skip generations

3. Affected individuals usually born to unaffected parents

4. If both are heterozygous then ~1/4 will be affected

5. More frequent occurrence with consanguineous marriages

5 Rules for X-linked Recessive Inheritance

1. Usually more males than females affected

2. ~1/2 of a carrier mother’s sons are affected

3. Affected sons usually born to unaffected mothers (skipping a generation)

4. Never passed from father to son (needs to pass the Y)

5. All daughters of affected fathers are carriers (needs to pass his X)

4 Rules for X-linked dominant inheritance

1. Both males and females affected, more often females

2. Affected male passes trait to all daughters and no sons (needs to pass Y, and daughters get his X)

3. Does not skip generations

4. Affected mothers if heterozygous pass trait to ½ of sons and daughters

2 Rules for Y-linked Inheritance

1. Always transmitted from father to son

2. Only males are affected

3. Does not skip generations

Define Genetic Mosaicism or Chimerism

Individuals whose cells hold different genetic constitutions, aka cells not from your mother and father (Example: mutations)

Define “Dizygotic” twins including details about DNA sharing and placenta.

Fraternal Twins - Two different eggs fertilized by two different sperm. Separate placenta and 50% shared DNA

Define “Monozygotic” twins including details about DNA sharing and placenta.

Identical twins - One fertilized egg that splits into two embryos. Share a placenta and 100% shared DNA

What problem does researching twins help fix for geneticists?

How can we tell how much the environment affects what the phenotype of the genome is? When you have two individuals with 100% of the same genome, any differences in their development helps show how the environment affects phenotypes.

How can adoption help solve the “Geneticists Problem”?

Adoption studies allow geneticists to differentiate between genetic and environmental influences on traits. By studying adopted individuals and their biological and adoptive families, researchers can evaluate the impact of genetics versus upbringing as adoptees differ from their biological parents and share environments with their adoptive families.

What is the definition of Concordance and what can it tell us?

% of twin pairs where both twins have the trait, which tells us how much genetics affects a trait. If identical twins have a less than or similar % than fraternal twins, it shows that environment affects the trait more than the genome.

If concordance of asthma among monozygotic twins is 65% and dizygotic twins is 37%, what can you conclude?

Genetics is a large factor to the development of the trait..

If concordance of cancer among monozygotic twins is 5% and dizygotic twins is 7%, what can you conclude?

Environment is a more important factor than genetics to the development of the trait.

If you don’t have a 1:1:1:1 Ratio, 1:1 ratio, or >50%, <50% ratio, what can you conclude about the test cross outcome linkage?

This is incomplete linkage.