Lectures 9 & 10Founder Effects, Inbreeding and

MutationBob Verity

Summary of Lectures 7 & 81) Defined our terms

– Gene, Locus, Allele, Genotype, Phenotype, Gamete, Zygote, Dominant, Recessive

1) Introduced genetic drift– Stochastic change in allele frequencies– Can lead to fixation or loss of alleles.– Stronger in small populations, eg. in founder events.

1) Touched on Selection– Selection occurs against a background of drift– Related to ‘fitness’ of a particular genotype

Any Questions?

Lecture Outline

1) The Amish

2) Inbreeding and Identity by Descent

3) Mutation

The Amish

• The Amish are an Anabaptist Christian denomination in the United States and Ontario, Canada

• Known for their plain dress and limited use of modern devices such as automobiles and electricity

• Most speak a German dialect known as Pennsylvania Dutch

The AmishTwo key concepts for understanding Amish practices are their revulsion toward Hochmut (pride, arrogance, haughtiness) and the high value they place on Demut or "humility" and Gelassenheit (calmness, composure, placidity) often translated as "submission" or "letting-be”. The Amish anti-individualist orientation is the motive for rejecting labor-saving technologies that might make one less dependent on community; or which might start a competition for status-goods.

The AmishThere are approximately 12,000 Amish in Lancaster county. They are descended from about 400 founders originating from the Swiss German border with very little recruitment from other populations. The few converts are well documented.

The AmishOver the generations the number of descendants of these few founders has grown and the population has therefore expanded (although more people leave the community than join).

• excellent records• large family size• restricted population

highly valuable for genetic studies

1,225,366 names!386,130 families!

The Genetics of Amish Populations

"Only about 200 Amish founders came from Europe to the United States in the early 1700s," Shuldiner notes. "The Amish population has grown to 30,000 in the localized area of Lancaster County. While diabetes does not occur more frequently in the Amish than in other population groups, the Amish are a closed population with a fixed gene pool, have very large families, and essentially complete genealogies dating back 14 generations. It's quite a unique situation to be able to study a specific group of people who have particularly good characteristics for genetic research."

Alan R Shuldiner M.D.

The Genetics of Amish PopulationsThe allele frequencies in the Amish population are atypical of the communities from which they are descended in Europe because of…

1. Founder events: the first 400 (or so) founders will have, by chance, had an atypical collection of genes

2. Further drift: the small population size subsequent to foundation will have lead to further genetic drift.

The Genetics of Amish PopulationsSix of the founders names are responsible for 3/4 of those seen today and a full 1/4 are called Stoltzfus!

As names are unlikely to confer a selective advantage, this change in the frequency of names is most easily explained as a random or stochastic change. (Be careful: they might be associated with genes that confer a selective advantage). The same change would be predicted for Y chromosomes which are also transmitted down the paternal line, and a similar change for mitochondrial DNA which is passed down the maternal line.

The Genetics of Amish Populations• Wilma Bias (John Hopkins University) looked at 30-35 genetic systems

giving evidence about 100-150 loci from one blood sample. The loci range from the well known blood groups to soluble enzymes.

• It is important to remember that, by chance some loci will have larger changes in allele frequency, some smaller – although those on the Y chromosome and mitochondria would be expected to show greater changes.

• Like the names, some loci show dramatic frequency changes since foundation 15%-25% in the case of Rh -ve.

The Genetics of Amish PopulationsIt is particularly important for expectant mothers to know their blood's Rh factor. Occasionally, a baby will inherit an Rh positive blood type from its father while the mother has a Rh negative blood type.

The baby's life could be in danger if the Rh negative mother's immune system attacks the baby's Rh positive blood. If this happens, an exchange transfusion may save the baby's life. The baby's blood can be exchanged for new blood that matches the mother's.

Rh –ve is almost certainly selected against

The Genetics of Amish Populations

Q1) Why would we expect to see greater genetic drift on the Y chromosome compared with other parts of the genome?

Questions

Q2) How can Rh –ve have reached high frequency when it is selected against?

A) Smaller effective population size

A) Drift acts on all loci,Even those subject to selection

The Genetics of Amish PopulationsEllis-van Creveld syndrome (know colloquially as “Six fingered dwarfism”) is a recessive trait: genealogical studies show that it is only expressed when an individual carries two copies of the allele.

Extremely rare in the population at large, however…

…estimates are that 1/7 of the present day Amish population carry the gene

Perhaps only 1 of the 400 founders carried the allele in the ancestral population (in a single copy, hence the allele frequency would have been 1/800). The allele may have subsequently drifted to high frequency.

The Genetics of Amish PopulationsThis syndrome was described by Ellis and van Creveld in 1940. Very few cases have been reported in the literature.

A follow up study was carried out by McKusic et al. in 1964, which focussed on the Amish population. Almost as many affected individuals were found in this one kindred as had been reported in all the medical literature up to that time

McKusic et al. estimated that around 5 in 1000 Amish births resulted in EvC. From this they estimated the frequency of heterozygous carriers at around 13%.

The Genetics of Amish PopulationsHow did they arrive at these numbers?

Let us call the EvC allele the ‘A’ allele and any non-EvC allele the ‘B’ allele. We will use the symbol gAA to refer to the homozygous (affected) genotype frequency. This genotype frequency was estimated at gAA=0.005 from observed individuals and historical records

Under Hardy Weinberg proportions we would expect to see p2 homozygotes of this sort, where p is the allele frequency of the EvC allele. Thus, p2=0.005 and from this we can estimate that p≈0.07

Again, assuming Hardy Weinberg proportions we would expect the genotype frequency of heterozygotes to be gAB=2p(1-p), which works out at around gAB≈0.13

The Genetics of Amish Populations

Notice that the proportion of carriers (gAB≈0.13) is much larger than the proportion of affected individuals (gAA=0.005 ).

Why might we generally expect to see this pattern in recessive diseases?

The Genetics of Amish PopulationsBrief summary…

•The Amish are a text-book example of genetic drift.

•A number of disadvantageous alleles have drifted to high frequency, in spite of the action of selection against them. This reminds us that genetic drift affects all loci, not just those that are evolving neutrally.

•Detailed records combined with a polite culture open to conversation with scientists means that we can investigate genotype and allele frequencies for certain conditions that would otherwise be hidden from view.

Lecture Outline

1) The Amish

2) Inbreeding and Identity by Descent

3) Mutation

Inbreeding and Identity by DescentGenetic drift causes allele frequencies to change over time as a result of sampling from a finite population. However, genotype frequencies are expected to remain in Hardy Weinberg proportions every generation.

What can cause a deviation from these proportions is inbreeding: defined as non-random mating of relatives leading to the increased probability of identity by descent.

The Amish actually avoid cousin matings (and closer), so the population is actually less inbred that you would expect from a random mating population.

Inbreeding and Identity by DescentGlobal distribution of marriages between couples related as second cousins or closer

Inbreeding and Identity by DescentThe probability of identity by descent due to relatedness between parents can be measured by the parameter f.

In simple terms, f is the chance that the two gene copies in a diploid individual are descended from the same copy in an earlier generation.

The greatest possible amount of inbreeding occurs in self-fertilisation.

In this case the two gene copies in the offspring have a probability f=1/2 of originating from the same copy in the parent.

Inbreeding and Identity by DescentConsider an infinitely large population of selfing diploids. Assume that every individual in the starting population is a heterozygote.

Genotype frequencies change over generations until eventually we would be left with only homozygotes. Notice that the allele frequencies have not changed from the initial frequency of p=1/2.

Inbreeding and Identity by DescentIn more complex forms of inbreeding the coefficient f can still be worked out by looking at pedigrees.

In this example the probability of identity by descent comes out at f=1/8.

Inbreeding and Identity by DescentWord of caution: The word inbreeding is a bit “fuzzy”

Some people include genetic drift as a sort of inbreeding, others do not.Better to contrast genetic drift against consanguinity.

Drift and consanguinity are similar in some ways, and complete opposites in others!•Both occur due to a build up of shared ancestry within a population.•Drift occurs as a result of finite population size, whereas consanguinity could technically occur even in an infinitely large population.•Drift results in a change in allele frequencies, but genotype frequencies remain in HWE. Consanguinity results in a change in genotype frequencies, but does not alter allele frequencies.

These two processes have different implications for eg. disease

Inbreeding and Identity by Descent

BottleneckThose deleterious recessive alleles that

drift up produce increased incidence of the disorder. This is then reduced

by selection over subsequent generations.

ConsanguinityThe incidence of each disorder is increased, but selection reduces the incidence rapidly.

Questions?

Announcements• Additional reading for

these lectures: ‘Evolution’ by Barton et al, Part III. Available in the library

Announcements• There will be a practical in week 9 to accompany my

lectures. In this practical we will use the progam PopG.• The practical is preceded by a mini-exam on

Wednesday 6th March in which you must…1) Show your notes on the video ‘How evolution really works, Part

1’, available on youtube2) Demonstrate that you are comfortable using the program PopG.

• Full details of how to access the program and what you will be tested on can be found on the course website. PLEASE READ THESE DETAILS

• If you fail either point 1) or 2), or if you fail to attend, then you will have to come back for a remedial session (more work)

Lecture Outline

1) The Amish

2) Inbreeding and Identity by Descent

3) Mutation

MutationConsider the following questions…

1) What is mutation?2) What are some ways of classifying

mutation?3) How does mutation interact with

drift and selection?

Mutation

Mutation•The processes producing genetic variation

•The original source of all genetic variation

•A permanent structural alteration in DNA

In most cases, DNA changes either have no effect or cause harm, but occasionally a mutation can improve an organism's chance of surviving and passing the beneficial change on to its descendants.

MutationSubstitutionOne base exchanged for another

InsertionExtra base pair(s) inserted

DeletionBase pair(s) lost

Frameshift

Applies to insertions and deletions. Anything which changes the amino acid sequence being coded for

Mutation

There are also some larger mutational events that can occur, including…

•Large-scale deletion/insertion events

•Duplication

•Inversion

•Translocation

and some very large…

•Polysomy

•Whole genome duplication

Mutation

Without some process generating variation, eventually all alleles will become either fixed or lost over enough time

Mutation

Mutation can re-introduce lost genetic variation into a population

Mutation

• Each gene copy experiences mutation at a rate μ

• In a population of 2N genes this is a total mutation rate of 2Nμ

• The chance of any one new allele going to fixation is 1/2N

• Therefore…the probability of a new mutant allele going to fixation under drift alone is 1/2N * 2Nμ = μ

The rate of substitution is independent

of the population size

Mini Revision SessionShort questions…

1.Define the terms Dominant and Recessive.

2.How are relative and absolute fitness calculated?

3.Is genetic drift stronger or weaker in a small population? Why?

Longer questions…

1.Explain how random sampling from a finite population leads to stochastic changes in allele frequencies.

2.Why do we expect many more carriers of recessive deleterious alleles than affected individuals?

3.What is the probability of identity by descent (f) of an offspring of full sib parents (parents are brother and sister with the same mother and father)?

Mini Revision SessionI will not be providing model answers for all of the mini-revision session questions, as it is far more important that you think about these questions yourselves! All of the answers are contained within

the lecture notes of the past two weeks – once you familiarise yourself with this material these questions should seem fairly straightforward.

I will provide the answer for long question 3, so that you can check you got the right number…

Mini Revision SessionFirst things first; we need to draw a pedigree of the offspring of full sib parents.

One thing that was confusing people is that the question did not specify the genotypes of either the parents or the offspring. Remember that we are trying to work out the probability of identity by descent – in other words, the probability that the two genes in the offspring are descended from the same gene copy in an earlier generation. We do not need to know any genotypes to work this out! To make this point clear, I have drawn genes in the grandparents as dots, rather than letters.

Mini Revision Session1. We know that one gene copy in the

offspring came from the father, and one from the mother. The question is; where did each of these come from in the grandparental generation?

Mini Revision Session1. We know that one gene copy in the

offspring came from the father, and one from the mother. The question is; where did each of these come from in the grandparental generation?

2. Looking just at the paternal side, there is an equal chance that this gene came from any of the 4 gene copies in the grandparents. Thus, we can say that the probability of each of these events is ¼.

Mini Revision Session1. We know that one gene copy in the

offspring came from the father, and one from the mother. The question is; where did each of these come from in the grandparental generation?

2. Looking just at the paternal side, there is an equal chance that this gene came from any of the 4 gene copies in the grandparents. Thus, we can say that the probability of each of these events is ¼.

3. The same is true of the maternal side. The probability of this gene descending from each of the genes in the grandparents is ¼.

Mini Revision Session4. Combining this knowledge, we can work

out the probability that both offspring genes are descended from the same copy. Looking at the first grandparental gene (ie. the first black dot), we know that the probability of both the maternal and paternal genes coming from here is ¼ × ¼ = 1/16.

Mini Revision Session4. Combining this knowledge, we can work

out the probability that both offspring genes are descended from the same copy. Looking at the first grandparental gene (ie. the first black dot), we know that the probability of both the maternal and paternal genes coming from here is ¼ × ¼ = 1/16.

5. The same is true of the second grandparental gene (second black dot). In fact, this is true of any of the 4 grandparental genes.

Mini Revision Session6. In summary; there are 4 ways that the

offspring genes could be descended from the same gene copy. Each of these has probability 1/16. Thus, the overall probability of identity by descent is…

1/16 + 1/16 + 1/16 + 1/16 = 4/16

Or

f = 1/4