15 Mendelian Inheritances in Man

Tabitha Panmei

Table of Contents

1.      Introduction

2.      Mendel’s law

a)      Law of Segregation (the First Law)

b)      Law of Independent Assortment (the Second Law)

c)      Law of Dominance (the Third Law)

3.      Mendelian Traits and Non-Mendelian Traits

4.      Background Information

5.      Genetic Mapping of Mendelian characters

6.      Mendelian and Atypical patterns of inheritance

7.      Useful genetics Vocabulary

8.      Misconception Regarding Dominance and Recessiveness

9.      Mendelian Inheritance in man and its online version, OMIM

Learning Outcomes of the study

After studying of this module:

• You shall be able to understand how Mendelian inheritance first discovered and the important role play in human body.
• Shall understand the difference of Mendelian traits and Non-Mendelian traits.
• You would be able to identify the differences of dominant and recessive inheritance occurred in man.
• You would be able understand how the hereditary diseases occur through generation to another.
• You would be able to understand how Mendelian Inheritance in man and its online version, OMIM.

1. Introduction

Mendelism is the system of heredity formulated from Mendel’s conclusions. Gregor Mendel is known as the father of modern genetic because of his experiment with pea plants which gave the basic insights and vocabulary to pattern of genetic .Briefly summarized, as we understand it today by means of the science of genetics, the mendelism system states that an inherited characteristic is determined by the combination of a pair of hereditary Units, or gene, one from each of the paternal reproductive cells, or gametes. Mendel used a statistical analysis of large populations of plant offspring to identify all possible expressions of basic genetic trait. More than 11,000 Mendelian disordered have been revealed. Mendelian disorders have been propounded by Australian botanist Gregor Mendel (1822,84). Mendel’s developed some of the concepts that we now. Some of the terms are given below:

Table 1.1 showing Mendel concepts

Dominant	Express even if only one factors is inherited from one parent.
Recessive	Inherit one factor from each parent in order for expression to occur.
Allele	Different forms of the same gene.
Homozygous	Offspring inherit matching alleles, one from each parent.
Heterozygous	Offspring inherit non-matching alleles, one from each parent.
Genotype	The sum of all genes, many which will not ever be expressed.
Phenotype	The part of the genetic constitution that is expressed.

Humans are not so simple and although many of their traits are dominant or recessive patterns, many others are multiple alleles, co-dominant, or other expressedpatterns. Mendelian inheritance is based on transmission of a single gene on a dominant recessive or X-linked pattern.

Mendel’s Genetics

For thousands of years farmers and herders have been selectively breeding their plants and animals to produce more useful hybrid. It was somewhat of a hit or miss process since the actual mechanisms governing inheritance were unknown. Knowledge of these genetic mechanisms finally came as a result of careful laboratory breeding experiments carried out over the last century and a half. By the 1890’s, the invention of better microscopes allowed biologists to discover the basic facts of cell division and sexual reproduction. The focus of genetics research then shifted to understanding what really happens in the transmission of hereditary traits from parents to children. A number of hypotheses were suggested to explain heredity, but Gregor Mendel, a little known Central European monk, was the only one who got it more or less right. His ideas had been published in 1866 but largely went unrecognized until 1900, which was long after his death. His early adult life was spent in relative obscurity doing basic genetics research and teaching high school mathematics, physics, and Greek in Bruno. In his later years, he became the abbot of his monastery and put aside his scientific work.

While Mendel’s research was with plants, the basic underlying principles of heredity that he discovered also apply to people and other animals because the mechanisms of heredity are essentially the same for all complex life forms.While Mendel’s research was with plants, the basic underlying principles of heredity that he discovered also apply to people and other animals because the mechanisms of heredity are essentially the same for all complex life forms.

1.      Mendelian Law’s

a)   Law of Segregation (the First Law)- The law of Segregation states that every individual contains a pair of alleles for each particular trait which segregate or separate during cell division (assuming diploid) for any particular trait and that each parent passes randomly selected copy (allele) to its offspring. The offspring then receives its own pair of alleles of the gene for that trait by inheriting sets of homologous chromosomes from the parent organisms. Interaction between alleles at single locus termed dominant and these influence how the offspring expresses that trait. During game, the allele for each segregation from each other so that gametes carries only one allele for each gene.

b)   Law of Independent Assortment (the Second Law)-It is state that in the inheritance of more than one pair of traits in a cross simultaneously, the factors responsible for each pair heritance Law of traits are distributed to the gametes. The law of Independent Assortment, also known as Inheritance Law which states that separate genes for separate traits are passed dependent and independently of one another from parents to children. The biological selection of a particular gene in the gene pair for one trait to be passed to the offspring has nothing to do with the selection of the gene for any other trait. More precisely, the law state that if the different allele genes assort independently of one another during gamete formation. Genes for different traits can segregate independently during the formation of gametes.

c)    Law of Dominance (the Third Law)-The third law state that recessive alleles will always be masked by dominant allele. A cross between homozygous dominant and homozygous recessive will always express the dominant phenotype, while still having a heterozygous genotype. It can explained easily with the help of a mono hybrid cross experiment. It is important to note that the law of dominance is significant and true but is not universally applicable. According to the latest revisions, only two of the rules are considered to be laws. The third one is considered as a basic principle but not a genetic law of Mendel. Some alleles are dominant while other recessive, an organism with at least one dominant allele will display the effect of the dominant allele.

2.   Mendelian Traits:

In earlier studies, some physical attributes of humans were considered Mendelian in nature, but further study suggested they are in fact not. These traits may involve more complex genetic models that usually include more than one gene. Mendelian traits are passed on to the offspring through the recessive pattern of inheritance or through the dominant pattern. The recessive inheritance pattern needs both parents to have the genes, and offspring must inherit a gene from each parent to display the trait. Through the dominant pattern of inheritance, only one copy of the gene needs to be inherited by a child to display the trait. In the case of autosomal genes the child can inherit the gene from either parent. Mendelian Traits are traits which follow Mendel’s rules of only two possible versions (dominant and recessive traits).

Table2.1.Showing Mendelian traits characteristic

3.    Non-Mendelian trait:

Mendel explained inheritance in terms of discrete factors- gene- that are passed a long from generation to generation according to the rules of probability. Mendel’s laws are valid for all sexually reproducing organisms, including garden peas and human beings. However, Mendel’s law stop short of explaining some patterns of genetic inheritance. For most sexually reproducing organisms, cases where Mendel’s laws can strictly account for the patterns of inheritance are relatively rare. Often the inheritance patterns are more complex. The F1 offspring of Mendel’s pea crosses always looked like one of the two parental varieties. In this situation of “complete dominance”, the dominant allele had the same phenotype effect whether present in one or two copies. But for some characteristics, the F1 hybrid had an appearance in between the phenotypes of the two parental varieties. In Mendelian inheritance, genes have only two alleles, such as a and A. In nature, such genes exist in several different forms and are there for said to have multiple alleles.

4. Background Information

Mendel’s laws were first tested in pea plants and fruits flies, evidence quickly mounted that they applied to all living things. Just as mutations had provided keys to understanding fruit fly genetics, pedigrees of families affected by diseases provided many of the first examples of Mendelian inheritance in humans.

Table1.3: Historical event of Mendelian inheritance in man

5.  Genetic Mapping of Mendelian Characters’

Genetic mapping is needed to localize genes underlying observable phenotypes, which cannot be identified by searching the DNA sequence of human genome. Genes that are physically close together on the same chromatid tend to travel together during meiosis; genes that are further apart are liable to separate through crossovers between homologous chromosomes. Genetic maps are co-linear with physical maps, but distances do not necessarily correspond because the probability of recombination per mega base o DNA is not uniform along the length of a chromosome, and differs between males and females. Genes are mapped by checking a collection of pedigrees for co-segregation of relevant phenotype and the alleles of genetic markers. The main markers used are short tandem repeat polymorphism (STRPs or microsatellites) and single nucleotide polymorphism (SNPs).In principle, genetic mapping in humans is exactly the same as genetic mapping in any other sexually reproducing diploid organism. The aim is to discover how often two loci are separated by meiotic recombination.

Example; the proportion of children who are recombinant is the recombination fraction between the two loci A and B. There are two ways which is recombinants and non-recombinants: Consider a person who is heterozygous at two loci and so types as A1A2 B1B2. Suppose the alleles A1 and B1 in this person came from one parent, and A2 and B2 from the other. Any of that person’s children who inherit one of these parental combinations (A1B1 or A2B2) is non-recombinant, whereas children who inherit A1B2 or A2B1 are recombinant

Fig 6.1.showing recombinants and nonrecombinants (www. Ncbi.nih.gov)

Alleles at two loci (locus A, alleles A1 and A2; locus B, alleles B1 and B2) are segregating in this family. Where this can be deduced, the combination of alleles a person received from his or her father is boxed. Persons in generation III who received either A1B1 or A2B2 from their father are the product of nonrecombinants sperm; persons who received A1B2 or A2B1 are recombinant. The information shown does not enable us to classify any of the individuals in generations I and II as recombinant or nonrecombinants, nor does it identify recombinants arising from cogenesis in individual II2.

Fig.6.2.The five stages of prophase in meiosis (source: www.ncbi.nlm.nih.gov)

If two loci are on different chromosomes, they will segregate independently. Considering spermatogenesis in individual II1 in Figure 11.1, at the end of meiosis I, whichever sperm

receives allele A1, there is a 50% chance that it will receive allele B1 and a 50% chance it will receive B2. Thus, on average, 50% of the children will be recombinant and 50% nonrecombinants. The recombination fraction is 0.5. If the loci are syntenic, that is if they lie on the same chromosome, then they might be expected always to segregate together, with no recombinants. However, this simple expectation ignores meiotic crossovers. During prophase of meiosis I, pairs of homologous chromosomes synapse and exchange segments. Only two of the four chromatid are involved in any particular crossover. A crossover, if it occurs between the positions of the two loci, will create two recombinant chromatids carrying A1B2 and A2B1, and leave the two noninvolved chromatids nonrecombinants. Thus one crossover generates 50% recombinants between loci flanking it.

Recombination will rarely separate loci that lie very close together on a chromosome, because only a crossover located precisely in the small space between the two loci will create recombinants. Therefore sets of alleles on the same small chromosomal segment tend to be transmitted as a block through a pedigree. Such a block of alleles is known as hhaplotype. Haplotype mark recognizable chromosomal segments which can be tracked through pedigrees and through populations. When not broken up by recombination, haplotype can be treated for mapping purposes as alleles at a single highly polymorphic locus.The further apart two loci are on a chromosome, the more likely it is that a crossover will separate them. Thus there combination is a measure of the distance between two loci. Recombination fractions define genetic distance, which is not the same as physical distance. Two loci that show 1% recombination are defined as being 1 centimorgan (cM) apart on a genetic map.

Fig 6.3.Single and double recombinants (source: www.ncbi.nih.gov)

Each crossover involves two of the four chromatids of the two synapsed homologous chromosomes. The black chromosome carries alleles A1 and B1 at two loci, while the blue chromosome carries alleles A2 and B2. Gametes in which the chromatid is the same color at the two loci are nonrecombinants for these loci, those where the chromatids are different colors are recombinant.(A) A single crossover generates two recombinant and two nonrecombinants chromatids. (B) A two-strand double crossover leaves flanking markers nonrecombinants on all four chromatids. (C) A three-strand double crossover leaves flanking markers recombinant on two of the four strands. (D) A four-strand double crossover generates 100% recombinants. The three types of double crossover occur in random proportions, so the average effect of a double crossover is to give 50% recombinants.

4.   Mendelian and Atypical patterns of Inheritance

Mendelian inheritance is based on transmission of single gene ondominant, recessive or X-linked patterns. Discovering on DNA structure, the genetic code, genome and the observation that some characters and heredity diseases do not follow classical Mendelian inheritance have led researchers to define other patterns of transmission, referring particularly to multifactorial and mitochondrial inheritance. There will undoubtedly be important advances in our knowledge of the pattern of inheritance of characters and diseaseses given a better understanding of gene structure and role, interaction of genes between them and with the environment.

Mendelian inheritance

• Autosomaldominant inheritance
• Autosomal recessive inheritance
• Sex-linked  inheritance

Autosomal dominant inheritance

Inheritance transmission on a dominant allele on an autosomal causes a trait to be expressed. Autosomal genetic inheritance pattern is an abnormal gene is dominant over the normal gene. The individual shows the characteristics associated with the abnormal gene. The inheritance pattern described a dominant trait or condition caused by a mutation in a gene on the X chromosome. The condition is expressed in heterozygous females as well as males, who have only one X chromosome. Affected males tend to have more significant disease than affected females. Disorders inherited in this manner are relatively rare.

Characteristic of Autosomal dominant inheritance

I) Both male and female are affected.

II) The disease is observed in multiple generations.

III)Transmission of the disease can be from both sex.

IV) Mutation in only one allele is enough to express the disease.

V)  Vertical transmission.

VI) The offspring 50% chance to have the disease.

Punnet’s square showing possible gamete combinations for an autosomal dominate allele

Fig.2. Punnet’s square (www.sellers.kippenjungle.nl)

Example diseases of Autosomal dominant are

·         Achondroplasia

·         Aniridia

·         Marfan syndrome

·         Steinert myotomic dystrophy

·         Polydachyly

·         Adenomatosous polyposis of the colon

Autosome Pedigree pattern

• In pedigree analysis, the main clues for identifying a dominant disorder are that the phenotype tends to appear in every generation of the pedigree and that affected fathers and mothers transmit the phenotype to both sons and daughters.
• It has been estimated that 1% of live-born infants carry a gene for an autosomal dominant disease; in 20% of these cases (0.2% of live-births) their disease is due to a new, or “sporadic” mutation that arose in the reproductive cells of one of their parents.
• More than 1,500 dominant diseases have been described in human Pedigree of a dominant phenotype determined by a dominant allele A. In this pedigree, all the genotypes have been deduced.

Fig.3.Pedigree pattern Autosomal dominant (source: www.biologyexams4u.com)

Autosomal recessive inheritance

The gene in question is located on one of the autosomes. These are numbered pairs of chromosome, 1 through 22. Autosome does not affect offspring gender. Recessive means that two copes that two cope of the gene are necessary to have the trait or disorder. Some of the autosomal recessive inheritance diseases are -Heredity breast and ovarian cancer, galactosemia, cystic fibrosis.

Some of the characteristic of autosomal recessive inheritance are:

I)  Both male and female are affected.

II)  The disease is observed in only single generation.

III)  Both gene alleles (homozygous) need to be affected in order to express the disease.

Example diseases of recessive inheritance are

• Glycogenosis ,VI types
• Sugar intolerance ; galactose, fructose, saccharose, lactose
• Mucopolysaccharidoses VI types, except Hunter disease MPSII which is RLX
• Most of Amino acid disorders: phenylketonuria sickle cell anemia, tyrosinosis, cystinosis, leucenosis, albibism variants

Autosomal recessive pedigree pattern

Two key points that distinguish pedigrees segregating recessive conditions are that generally the disease appears in the progeny of unaffected parents and that the affected progeny include both males and females equally. When we know that both male and female phenotypic proportions are equal, we can assume that we are dealing with autosomal inheritance, not X-linked inheritance. The following typical pedigree illustrates the key point that affected children are born to unaffected parents.

Fig.4.Pedigree pattern autosomal recessive(source: www.biologyexams4u.com)

Sex-linked inheritance

The pattern of inheritance that may result from a mutant gene to located on either the X or Y chromosome.

Sex linked inheritance have three types:

I) X-linked dominant

II)  X-linked recessive

III) Y-linked

X-linked dominant: The inheritance pattern describing a dominant trait or condition caused by a mutation in a gene on the X-chromosome. The condition is expressed in heterozygous females as well  as male, who have only one X-chromosome. Affected males tend to have more significant diseases than affected females. Disorders inherited in this manner are relatively rare.Vitamin D resistant rickets

X-linked recessive: It is a mode of inheritance in which a mutation in a gene on the X-chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation. The diseases are passed down through families one of the X or Y chromosome.

Y-linked:since Y chromosome is present only in males Threfore the traits are passed on to the son from father in this type of transmission that is to say All sons of an affected male are affected. Affected males always have affected fathers.

Example Sex-linked diseases are

·         Color blindness

·         Hemophelia A and B

·         Angiokeratosis (Fabry disease)

·         Duchenne muscular dystrophy

·         Incontinentiapigmientosum

·         Agammaglobulinemia, Bruton type

·         G6PD deficiency

Multifactorial inheritance: It is based on the synergy of genes and environmental factors. There are for one specific characters, a series of genes (and not loci) that form the basis of its identity (synonymous; polygenic system, quantitative inheritance, quantitative heredity, multiple factors).

Example Multifactorial inheritance diseases are

·         Cleft palate

·         Hare lip and cleft palate

·         Cardio-vascular diseases

·         Schizophrenia

·         Diabetes

·         Gout

·         Hip dislocation

·         Strabismus

Mitochondrial inheritance: The transmission of the mitochondrial genome from mother to child. Mitochondrial contain their own set of genes which are chiefly involved in metabolic processes. This is in addition to the genes in the cell’s nucleus. They have their own DNA and extra nuclear DNA cell presents. The disease is transmitted solely by women to all her descents. The genetic defect is not present in all but in some of a fraction of mitochondria which transmitted to generation to next then according to the number of gene mutation in mitochondria.

Example mitochondrial inheritance diseases are

·         Leber optic atrophy

·         Mitochondrial myopathies

·         Pearson syndrome

6.    Useful genetics Vocabulary

·         Homozygous and heterozygous

·         Genotype and phenotype

·         Monohybrid and dihybrid crosses

·         Testcross

8. Misconception Regarding Dominance and Recessiveness

• Traditional methods of teaching genetics have leads to misunderstanding of dominant and recessive. People have the impression that these phenomena are all or nothing situations.
• The misconception specially pertains to recessive alleles, and the general view is that when this allele occurs in carriers, they have no effect on the phenotype. They are completely inactivated by other allele. Sometime it effect on phenotype but not through observable.
• Similarly misconception relate to dominant allele. Most people see dominant allele somehow stronger or better and there is always mistaken that dominant allele are more common in population.
• The relationships between recessive and dominant alleles and their functions are complicated than they first appear. Previously held views of dominant and recessive were guided by technologies but in fact, dominant and recessive will remain important factors in genetics, it clear that the away in which these concepts will be taught and adapted accommodate new discoveries.

9.    Mendelian Inheritance in man and its online version, OMIM

Online Mendelian Inheritance in man (OMIM) is a continuously updated catalog of human genes and genetic disorders and traits with particular focus on the molecular relationship between genetic variation and phenotypic expression. Which focus on molecular relationship between genetic variation and phenotypic variation? Thus it considered to be a phenotypic companion to the Human Genome Project. OMIM is a continuation of Dr. Victor A. McKusick’s Mendelian Inheritance in Man, which was published through 12 editions, the last in 1998. OMIM is currently biocurated at The Medicine School.

OMIM database used a specific six- digit numbering system Autosomal loci or Phenotypes: 1-(10000-) 2-(200000-)

i.   X-linked loci or phenotypes: 3-(300000-)

ii.  Y-linked loci or phenotype: 4-(400000-)

iii. Mitochondrial loci or phenotypes: 5-(500000-)

iv.  Autosomal loci or phenotypes: 6-(600000-)

Symbols providing MIM number represent

•  An asterisk (*) before an entry number indicates a gene.
• A number symbol (#) before an entry number indicates that it is descriptive entry, usually of phenotype, and does not represent a unique locus. The reason for the use of the any gene(s) related to the phenotype resides in another entry (ies) as described in the first paragraph.
• A plus sign (+) before an entry number indicates that the entry contains the description of a gene of Known sequence and a phenotype.
• A percent sign (%) before an entry number indicates that the entry describes a confirmed Mendelian phenotype or phenotypic locus for which the underlying molecular basis is not known.
• No symbol before an entry number generally indicates a description of a phenotype for which the Mendelian basis, although suspected, has not been clearly established or that the separateness of this phenotype from that in another entry is unclear.
• A caret (ᶺ) before an entry number means the entry no longer exists because it was removed from the database or moved to another entry as indicated.

And some of the other symbols are also used.

Mutations catalogued in OMIM

Mutations are catalogue in OMIM in the Allelic Variations section of gene entries. For most genes, only selected mutations are included. Include the first mutation to be discovered, high population frequency, distinctive phenotype, historic significance, unusual mechanism of mutation, unusual pathos-genetic mechanism, and distinctive inheritance (e.g., dominant with some mutations, recessive with other mutations in the same gene). Most of the allelic variants represent disease- causing mutations. A few polymorphisms are included, many of which show a positive correlation with particular common disorders.

Summary

• Gregor Mendel is called the father of modern genetic because his experiments with pea plants gave us the basic insights and vocabulary to accurately study genetic patterns.More than 11,000 Mendelian disordered have been revealed.
• Mendelian inheritance is based on transmission of a single gene on a dominant recessive or X-linked pattern.
• Mendel studied dichotomous traits of pea plant.
• Two type of mendelian inheritance in human.
• Autosomal and sex-link inheritance are found in Mendelian inheritance in human.
• Dominant and recessive inheritance also there.
• Homogygous, heterozygous, genotype, phenotype, monohybrid cross, dihybrid cross and testcross are some of the genetic vocabulary use in genetic inheritance.
• Mendelian Genetics problem are occur during monohybrid crosses and dihybrid crosses

References

Suggested Reading

• Berry, L. (2010). Understanding Humans Introduction to Physical Anthropology and Archeology (tenth edidition). Wadsworth,cengage Learning
• Jurmain,  R.,  Kilgore,  L.,  Trevathan,  W.,  &  Ciochon,  R.  L.  (2000). Introduction  to  physical  anthropology. Wadsworth.