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GENETICS ACTIVITIES FOR FOUNDATIONS OF BIOPSYCHOLOGY

Inés Moragrega (Coord.)

Raquel Costa (Coord.)

Patricia Mesa-Gresa Noemí San Miguel Raúl Ballestín Concepción Blasco Miguel Ángel Serrano Matthew Paul Lennol Ferran Suay

ISBN: 978-84-1147-311-8

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GENETICS ACTIVITIES FOR FOUNDATIONS OF BIOPSYCHOLOGY

AUTHORS: Inés Moragrega (Coord.)

Raquel Costa (Coord.)

Patricia Mesa-Gresa Noemí San Miguel Raúl Ballestín Concepción Blasco Miguel Ángel Serrano Matthew Paul Lennol Ferran Suay

INDEX Introduction

9

Legend

10

Punnet Square

11

1. Autosomal Unifactorial Inheritance

14

Activity 1.1. Dominant Autosomal Inheritance

14

Activity 1.2. Recessive Autosomal Inheritance

18

2. Sex-Linked or Gonosomal Unifactorial Inheritance

21

Activity 2.1. Sex-Linked Dominant Inheritance

21

Activity 2.2. Sex-Linked Recessive Inheritance

23

3. Combined Activities of Monogenic Inheritance

28

4. Quantitative or Polygenic Inheritance

35

Activity 4.1. Heritability: Nature vs Nurture

35

Activity 4.2. Behavioural Genetics: 10 Repeatedly Verified Results

38

Activity 4.3. Schizophrenia

45

Activity 4.4. Alcoholism

46

5. Epigenetics

49

Activity 5.1. What are we referring to when we talk about Epigenetics?

49

Activity 5.2. The Dutch famine: effects on the foetus and subsequent generations

52

Glossary

54

References

62

Notes

63

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INTRODUCTION How to work with this notebook This genetics activity workbook aims to serve as a way to practice Genetics problems and activities for which students frequently seek solutions and assistance within the Foundations of Biopsychology subject of the Psychology Degree of the University of Valencia.

The activities in this manual are organized according to the type of inheritance that is affected, whether it depends on one or several genes, whether it is sex-linked or not, and whether or not it is dominant. It is intended to address the problems of each type of inheritance from a practical point of view, using real-life problems with common or known diseases.

The activity notebook is designed to be completed autonomously and independently by the student once the theoretical concepts have been explained in class. The progress will depend on the dedication of each student, under the supervision of the professor.

The notebook covers the entire genetics syllabus contemplated in the teaching guide, although the teacher could, depending on the case, provide additional or complementary material according to specific needs through the Virtual Classroom. At the end of the booklet, a glossary is provided that includes the essential terminology of genetics and behavioural genetics to help understand the concepts and to solve any doubts. It’s convenient to pay attention to the glossary, in addition to completing the exercises in the glossary itself that are indicated in the topics.

Practical classes constitute an integral part of the student's education within the framework of the European Higher Education Area. Following the Bologna guidelines in this framework, the practical activities proposed here have been designed to facilitate the student's autonomous learning, thus promoting greater participation and responsibility in the acquisition of knowledge, skills and abilities.

This material is the collective result of the extensive teaching experience of the authors, who for years have faced the difficult task of introducing first-year students to the subject of Foundations of Biopsychology. The preparation of this notebook responds to the need to facilitate this task for students and teachers. We hope that this manual will contribute to achieving that goal.

THE AUTHORS

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LEGEND Below you will find the legend that will be used throughout this notebook and that will serve as a reference for carrying out activities that include family trees.

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PUNNET SQUARE Mendel established the three principles of inheritance: the law of Uniformity, the law of Independent Combination and the law of Segregation by considering the patterns of the results of monohybrid crosses of pea plants. The physical appearance of a certain character is called PHENOTYPE, and when the alleles are written in pairs to represent the two factors present in any individual we call it GENOTYPE. By convention, the first letter of the recessive character can be taken to symbolize the character in question, for example, we take the letter “b” to designate the low allele and “B” to designate the high allele. You will soon understand what the concepts "high" and "low" mean. If we combine all the possibilities in pairs we will have: BB, bb and Bb: the first two combinations are homozygous and the last one will be heterozygous for that character. In this sense, phenotypically two individuals will be tall (BB and Bb) and one short (bb), proportionally ¾ and ¼, respectively, but where did such proportions come from and why?

The Punnett Square method, named after Reginald Punnett, an important English geneticist, is very useful for learning genetics and for solving problems and calculating proportions. The gametes of the mother are represented in the columns and those of the father in the rows. From here, the next generation can be predicted by combining the characters of each of them, so this process will represent all possible random fertilization events. Below (Figure 1) an example is presented:

Mother

B

b

B

BB

Bb

b

bB

bb

Father

Genotype: 1 BB (1/4), 2Bb (2/4) and 1bb (1/4)

Phenotype: 3/4 tall and 1/4 short

Figure 1: Example of a Punnett Square. The gametes of the mother are represented in the columns and those of the father are represented in the rows. The bottom rows indicate the proportion of genotypes and phenotypes (Adapted from Klug, Cummings, Spencer and Palladino, 2013).

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Taking into consideration everything that was explained above, solve the following problem.

1. Dark hair colour (D) is dominant over blonde hair (d). Curly hair (C) is dominant over straight hair (c). Make all the possible combinations for both curly/straight and dark/blonde characteristics and calculate the genotypic and phenotypic ratios.

In the first Punnett Square (Figure 2) make all the possible combinations, and in the second (Figure 3) extract the different proportions.

Square 1

Father

Mother

Figure 2: Original design (Adapted from Klug, Cummings, Spencer and Palladino, 2013).

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Square 2

Phenotype

Phenotypic proportion

Genotype (write the genotype corresponding to the phenotype from the previous table)

Genotypic proportion

Dark and curly hair

Blonde and curly hair

Dark and straight hair

Blonde and straight hair

Figure 3: Original design (Adapted from Klug, Cummings, Spencer and Palladino, 2013).

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1. AUTOSOMAL UNIFACTORIAL INHERITANCE ACTIVITY 1.1. DOMINANT AUTOSOMAL INHERITANCE Please fill in the space in the glossary corresponding to the definition “Autosomal dominant”.

EXERCISE 1.1.1.

Huntington's disease or chorea is a progressive neurodegenerative pathology, characterized by motor dysfunctions (abnormal movements such as tics, balance and gait disturbances), behavioural disorders (affective disorders, depression or psychosis) and cognitive impairment (deficit in executive functions, learning and memory) that often ends in dementia. It affects between 5 and 10 people per 100,000 inhabitants in Western countries. The HD (Huntington’s Disease) gene was mapped to chromosome 4p16.3 in 1983. The mutation is a characteristic expansion of CAG triplets encoding the huntingtin protein, which interacts with proteins involved in the expression of a variety of cellular processes and genes, and is essential for both brain development and DNA repair processes. The more abundant the CAG repeats are, the earlier and more severe the clinical course will be (the presence of less than 28 repeats will not lead to the development of the illness, whereas more than 39 repeats will). Torres Leon et al. (2016) presented Huntington's disease through a case study (III-8) of a 52-year-old patient with a personal history of health problems and family members with Huntington's disease, who came to the clinic after presenting depression crises for the last 3 months, frequent irritability, and hand tremors for the last month. Physical examination revealed tremors in the hands when resting, as well as increased blinking. The case was consulted with the internal medicine specialist, who agreed on the diagnosis and referred it to the neurology specialist who had treated several cases in the same family (IV-4 and IV-8), corroborating the diagnosis of Huntington’s disease in both members (in addition to some cases of suicide, compatible with the depressive symptomatology of the disease). It is assumed that all deceased family members suffered from the disease. The case is discussed with the genetic counselling unit and the family genealogical tree is made (Figure 4), in order to search for the origin of the disease.

Figure 4: Genealogical tree extracted from Torres León et al., 2016.

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Using the genealogical tree, answer the following questions: 1. Are there skips between generations or do cases appear in all of them? _______________________________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ 2. When an affected member appears, does he/she transmit the disease to all his/her children?

YES/NO. 3. Is there a similar number of men and women affected? YES/NO. 4. Are there any cases of unaffected father/mother transmission to their offspring? YES/NO. 5. Are there any cases of father-to-son transmission? YES/NO 6. What implications do these findings have? __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ 7. Can a parent who does not present the disorders pass it on to their offspring? YES/NO 8. Study the cases of all the generations in more detail: which carriers of the disorder have you identified? __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ 9. Indicate the genotype of all the individuals of the first and second generations of the family tree. __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ 10. Taking everything you have analysed so far into consideration, indicate which is the most probable pattern of inheritance. Explain your answer. __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ 11. What is the probability of developing the disorder when one parent has Huntington's disease?

Justify your answer.

Select the correct option: 0% 50% 100% __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________

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12. To think about…

The diagnosis of Huntington's disease is confirmed with genetic testing. Currently, the fact that individuals at risk (with a family history) undergo genetic testing does not report a direct medical or clinical benefit, since there is no effective treatment for the disease. List some advantages and disadvantages of performing genetic diagnosis.

ADVANTAGES_______________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ DISADVANTAGES____________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ 13. Should individuals at risk be forced to undergo a genetic diagnosis? __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ 14. How could genetic counselling be approached? __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ Material to answer the questions:

https://seagen.org/ 16

EXERCISE 1.1.2.

Achondroplasia is a genetic alteration characterized by bone growth affectation that causes the shortening of the legs and arms, although the trunk is of a normal size. The altered gene in achondroplasia is the FGFR3 gene located on chromosome 4, responsible for encoding the fibroblast growth factor 3 receptor and is expressed in tissues such as cartilage, brain, intestine and kidneys, among others.

In this manner, we will take as an example the Lannister family from the series Game of Thrones.

Tywin Lannister is ashamed of his son Tyrion who manifests achondroplasia. However, his siblings do not have such a genetic alteration.

1. Fill in the following tree (Figure 5) with the genotypes of each of the possible descendants of Tyrion with a woman who did not present the alteration considering both genotypes.

Figure 5: Hypothetical genealogical tree for Tyrion Lannister of Game of Thrones. Original design.

In 80-90% of cases, achondroplasia is caused by a de novo mutation during spermatogenesis. The spermatozoa are altered and when they fertilize the egg they will form an embryo with a mutated copy of the FGFR3 receptor.

The remaining 10-20% of cases are due to hereditary transmission of the mutation as a ______________________ disorder. This means that in these cases achondroplasia is inherited from an achondroplastic parent.

2. Taking into consideration the type of inheritance, how likely would Tyrion be to pass the gene on to his offspring? ___________ %

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ACTIVITY 1.2. RECESSIVE AUTOSOMAL INHERITANCE Please fill in the gap corresponding to the definition “Autosomal recessive” in the glossary.

EXERCISE 1.2.1.

Cystic fibrosis is the most common potentially fatal genetic disease in the Caucasian population. It is diagnosed in about 1/3,300 Caucasian new-borns, 1/15,300 blacks, and 1/32,000 Asians.

Approximately 3% of the Caucasian population is considered to be a carrier of the trait, located on the long arm of chromosome 7, which encodes a membrane-associated protein, CFTR (Cystic Fibrosis Transmembrane Conductance Regulator). The most frequent mutation is the deletion (see structural anomaly in the glossary) of F508 and it only manifests itself in homozygotes. Heterozygotes may show subtle abnormalities but they are not clinically affected.

CFTR is a channel that controls the transport of chloride, sodium and bicarbonate across epithelial membranes, therefore the disease affects almost all exocrine glands. The main complications affect the lungs, with damage to the small and large airways and chronic and recurrent bacterial infections.

Other important consequences include malfunction of the pancreas, leading to poor absorption of nutrients and vitamins with consequent impairment of growth and development, and, in elderly patients, diabetes. In the film "Five Feet Apart" (2019) all these associated pathologies are well represented.

Raimundo (II-4) and Florinda (II-5) are second cousins (Figure 6), even so, they decided to apply for papal dispensation and get married. Five children were born as a result of the relationship. Raimundo has suffered from cystic fibrosis since he was a child, and, knowing the genetics of the illness, he was aware of the possibility that his children could be carriers. However, a few years later, his son Hermenegildo (III-1) and his daughter Margarita (III-2) began with multiple lung infections, so in genetic counselling they decided to carry out genetic screening on both of them and to extend it to the other members of the family.

Figure 6: Genealogical tree. Original design.

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Taking the family history and your knowledge about the inheritance of cystic fibrosis into account, answer the following questions: 1. What is the most likely pattern of inheritance? Explain your answer. __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ 2. Therefore, carriers must be (select the correct answer) Homozygous/Heterozygous, while those affected must be (select the correct answer) Homozygous/Heterozygous.

3. Which members of the family tree are definitely carriers? How many of Raimundo’s children are carriers? __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ 4. What reason can you use to ensure that it is NOT an autosomal dominant inheritance pattern? __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ 5. What reason can you use to confirm that it is NOT a sex-linked recessive inheritance pattern? __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ EXERCISE 1.2.2.

Juan, from Valencia, and Nala, who also lives in Valencia and is a daughter of Kenyan parents (black ethnicity), suffer from oculocutaneous albinism. They met in the ALBA association (association to people with albinism), hit it off quickly and after a couple of years they had their first daughter, Manolita. After her birth, the doctors confirmed that Manolita was not an albino. With his knowledge of genetics, Juan was very upset, since he knew that albinism is inherited in an autosomal recessive manner, leading him to believe that Manolita was not his daughter. After several discussions with Nala, who categorically denied her husband's hypothesis, they went back to the association to request genetic counselling and psychological support.

The diagnosis of albinism is usually clinical, through the observation of visual alterations and the lack or decrease of pigmentation in the skin, hair and eyes (or only in the eyes), but the mutations and gene or genes that cause the disorder are often ignored. However, a genetic diagnosis is the definitive test to confirm the alteration.

There are at least eight types of oculocutaneous albinism (OCA1 to OCA8). Type 1 albinism (OCA1) is the most common in general (incidence in Western populations: America and Europe 1/40,000). It is the characteristic albinism, with white hair, white or very pale pink skin, very light or red/pink eyes and visual acuity between 10-50% (caused by mutations or alterations in the TYR tyrosinase gene, on 19

chromosome 11). Type 2 oculocutaneous albinism (OCA2) is the most common type in black people of African origin. It is produced by mutations or alterations in the OCA2 gene (on chromosome 15), with a visual acuity of 20-30%. Therefore, not all albinos are carriers of the same mutation.

Answer the following questions: 1. Juan’s genotype: _________, Nala’s genotype: ________. Make a Punnett Square with the offspring of both parents. Is Juan right to be angry? __________________________________________________________________________________ __________________________________________________________________________________ _________________________________________________________________________________

2. Is there any possibility that Manolita is Juan and Nala’s daughter? How would you study it?

Justify your answer. __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________

3. What is the probability that Juan and Nala have an albino child? 0% 50% 100% What is the probability of them having a carrier child?

0% 50% 100%. Will the odds change depending on the sex of the child? YES/NO. Justify your answer. __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ 4. What is Manolita's genotype? Could she have children with albinism? Justify your answer. __________________________________________________________________________________ __________________________________________________________________________________ 5. Circle the correct option. In conclusion: The inheritance of albinism is: dominant/recessive and heterozygous/homozygous carriers do not have albinism, but can transmit it to their offspring.

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2. SEX-LINKED OR GONOSOMAL UNIFACTORIAL INHERITANCE ACTIVITY 2.1. SEX-LINKED DOMINANT INHERITANCE EXERCISE 2.1.1.

Fragile X syndrome is one of the most common heritable forms of mental retardation. It is caused by a mutation of the FMR-1 gene, located on the X chromosome, which results in the lack of FMRP protein, related to the activity of neurons and connective tissue. The alterations presented by those affected by this syndrome include cognitive alterations and/or mental retardation, physiological and physiognomic alterations, alongside developmental disorders and behavioural problems, among others. It should be noted that in women one of the two X chromosomes can be randomly inactivated, and as such, despite the fact that the woman is a carrier, if the chromosome that contains the syndrome is deactivated in favour of the unaffected one, they will be carriers of the disease, but they will not manifest the symptoms.

Considering the characteristics of the type of inheritance that defines Fragile X Syndrome, analyse the case presented below and answer the questions.

1. If in a couple, the mother is affected (heterozygous) and the father is healthy, what is the probability that their children will inherit the disease? Are there differences between sons and daughters? Would it be possible for there to be carrier daughters that are unaffected by the syndrome? What about sons? __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________

2. In the opposite case, meaning that the father is affected but the mother is not, what is the probability that their children will inherit the syndrome? Are there differences between sons and daughters? Would it be possible for there to be carrier daughters that are unaffected by the syndrome? What about sons? __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________ __________________________________________________________________________________

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