TNBGGA: The No Bullshit Guide to Genetic Analysis

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-<typo fs:x-large>Chapter 03: Defining genes by segregation patterns</typo>+<-chapter_02|Chapter 02^table_of_contents|Table of Contents^chapter_04|Chapter 04-> 
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 +<typo fs:x-large>Chapter 03: Defining %%genes%% by segregation patterns</typo>
  
 ===== Introduction ===== ===== Introduction =====
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 The classical definition of a gene is based on Mendel's Laws of Inheritance. Most genetics textbooks teach Mendelian genetics as a matter of course ("because it's how we've ALWAYS done things, duh!"), but there is an inherent danger in doing so. Mendel's view of genetics is very limiting because of what was known about genetics and biology in his day, and it is not uncommon for students that spend a lot of effort learning Mendel to become trapped into the same limiting world view.  The classical definition of a gene is based on Mendel's Laws of Inheritance. Most genetics textbooks teach Mendelian genetics as a matter of course ("because it's how we've ALWAYS done things, duh!"), but there is an inherent danger in doing so. Mendel's view of genetics is very limiting because of what was known about genetics and biology in his day, and it is not uncommon for students that spend a lot of effort learning Mendel to become trapped into the same limiting world view. 
  
-We discuss basic Mendelian genetics here in this chapter for several reasons. First, there is some value in understanding Mendel's analysis because it helps in further understanding meiosis ([[chapter_01|Chapter 01]]), an understanding of which is essential for learning all genetics. Second, we use classical Mendelian genetics in a more experimentally practical way as a vehicle to try to wean students off bad habits in learning genetics, including Mendelian notation and Punnett squares. We will deliberately choose Drosophila for our examples instead of pea plants (as is traditional when learning Mendelian genetics) to learn and use Drosophila genetic notation (what we refer to as fractional notation in this book), which is generally preferrable when discussing more advanced diploid genetics. Third, it is instructive to learn about Mendel's definition of a gene to see how ideas about genes have changed as scientists have learned more about genes. +We discuss basic Mendelian genetics here in this chapter for several reasons. First, there is some value in understanding Mendel's analysis because it helps in further understanding meiosis ([[chapter_01|Chapter 01]]), an understanding of which is essential for learning all genetics. Second, we use classical Mendelian genetics in a more experimentally practical way as a vehicle to try to wean students off bad habits in learning genetics, including Mendelian notation and Punnett squares. We will deliberately choose Drosophila for our examples instead of pea plants (as is traditional when learning Mendelian genetics) to learn and use Drosophila genetic notation (what we refer to as fractional notation in this book), which is generally preferable when discussing more advanced diploid genetics. Third, it is instructive to learn about Mendel's definition of a gene to see how ideas about genes have changed as scientists have learned more about genes. 
  
 Classical Mendelian genetics can be studied using yeast, but there are more powerful tools for analysis of yeast genetics (tetrad analysis) that will be discussed in [[chapter_13|Chap. 13]] and [[appendix_a|Appendix A]]. Mendelian genetics is more commonly used for analyzing obligate diploid organisms.  Classical Mendelian genetics can be studied using yeast, but there are more powerful tools for analysis of yeast genetics (tetrad analysis) that will be discussed in [[chapter_13|Chap. 13]] and [[appendix_a|Appendix A]]. Mendelian genetics is more commonly used for analyzing obligate diploid organisms. 
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-Table {{ref>Tab1}} above shows a genetic cross and analysis of its outcomes using a Punnett square. Many beginning students like using the Punnett square because it is intuitive, and it is also usually how they learned it in high school or earlier. As you start to learn more advanced genetic concepts, it is important to learn how to write genetic crosses for diploid organisms and their outcomes using "fractional notation". An example is given in Fig. {{ref>Fig2}} above. Genotypes are written similar to mathematical fractions, with the genetic contributions of each parent written in the "numerator" and "denominator". The "$\times$" symbol is used to indicate a cross, or a mating event. Parents are indicated using the "P" symbol (sometimes P0 is used), and subsequent generations of offspring use the symbols F1, F2, etc. At this point it may not be clear why "fractional notation" is better than using a Punnett square. You will soon see that Punnett squares work very poorly when crosses get more complex, and they also work poorly for thinking about crossing over, which we will see in [[chapter_05|Chapter 05]]. You can write genotypes in fractional notation either vertically as shown in Fig. {{ref>Fig2}}, or you can also write then horizontally (e.g., $shi^-$/$shi^-$) when typing, for instance (although you can also type vertical fractions now with most modern word processing/typesetting software such as Microsoft Word or [[https://www.latex-project.org/|$\LaTeX$]]). When writing horizontally, you can include parentheses or brackets to help reduce ambiguity: for example, ($shi^-$)/($shi^-$) or ($shi^-$/$shi^-$). In general, the vertical method is better and usually preferred. +Table {{ref>Tab1}} above shows a genetic cross and analysis of its outcomes using a Punnett square. Many beginning students like using the Punnett square because it is intuitive, and it is also usually how they learned it in high school or earlier. As you start to learn more advanced genetic concepts, it is important to learn how to write genetic crosses for diploid organisms and their outcomes using "fractional notation". An example is given in Fig. {{ref>Fig2}} above. Genotypes are written similar to mathematical fractions, with the genetic contributions of each parent written in the "numerator" and "denominator". The "$\times$" (pronounced "cross") symbol is used to indicate a cross, or a mating event. Parents are indicated using the "P" symbol (sometimes P0 is used), and subsequent generations of offspring use the symbols F1, F2, etc. At this point it may not be clear why "fractional notation" is better than using a Punnett square. You will soon see that Punnett squares work very poorly when crosses get more complex, and they also work poorly for thinking about crossing over, which we will see in [[chapter_05|Chapter 05]]. You can write genotypes in fractional notation either vertically as shown in Fig. {{ref>Fig2}}, or you can also write then horizontally (e.g., $shi^-$/$shi^-$) when typing, for instance (although you can also type vertical fractions now with most modern word processing/typesetting software such as Microsoft Word or [[https://www.latex-project.org/|$\LaTeX$]]). When writing horizontally, you can include parentheses or brackets to help reduce ambiguity: for example, ($shi^-$)/($shi^-$) or ($shi^-$/$shi^-$). In general, the vertical method is better and usually preferred. 
  
 ===== Complementation testing in obligate diploids ===== ===== Complementation testing in obligate diploids =====
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-<columns 100% *100%*> 
 <table Tab2> <table Tab2>
 +<columns 100% *100%*>
 +
 ^  possible F1 phenotype  ^  complementation?  ^  explanation  ^  inferred genotype  ^ ^  possible F1 phenotype  ^  complementation?  ^  explanation  ^  inferred genotype  ^
 |  not paralyzed  |  $shi^–$ and $par^–$ complement  |  $par^–$ genotype can supply function missing in $shi^–$ and vice versa  |  $\frac{par^-}{par^+} \cdot \frac{shi^+}{shi^-}$  |  |  not paralyzed  |  $shi^–$ and $par^–$ complement  |  $par^–$ genotype can supply function missing in $shi^–$ and vice versa  |  $\frac{par^-}{par^+} \cdot \frac{shi^+}{shi^-}$  | 
 |  paralyzed  |  $shi^–$ and $par^–$ do not complement  |  $par^–$ has lost function needed to restore $shi^–$; the $par^-$ mutant contains a mutant allele of $shi$  |  $\frac{shi^-}{shi^-}$  | |  paralyzed  |  $shi^–$ and $par^–$ do not complement  |  $par^–$ has lost function needed to restore $shi^–$; the $par^-$ mutant contains a mutant allele of $shi$  |  $\frac{shi^-}{shi^-}$  |
 +</columns>
 <caption>  <caption> 
 Possible outcomes and inferred genotypes from Fig. {{ref>Fig3}}. The "dot" separating the two “fractions” is an informal symbol to separate two different gene symbols where their linkage is unknown. For now, it's just a temporary symbol used to separate two different gene symbols. We will learn about linkage in [[chapter_05|Chapter 5]]. Possible outcomes and inferred genotypes from Fig. {{ref>Fig3}}. The "dot" separating the two “fractions” is an informal symbol to separate two different gene symbols where their linkage is unknown. For now, it's just a temporary symbol used to separate two different gene symbols. We will learn about linkage in [[chapter_05|Chapter 5]].
 </caption> </caption>
 </table> </table>
-</columns> 
  
 If $par^-$ and $shi^-$ complement, this means we can think of the parents in Figure {{ref>Fig3}} as having the genotypes $\frac{par^-}{par^-} \cdot \frac{shi^+}{shi^+}$ and $\frac{par^+}{par^+} \cdot \frac{shi^-}{shi^-}$. On the other hand, if $par^-$ and $shi^-$ do not complement, this implies that $par^-$ and $shi^-$ are mutant in the same gene (i.e., $par = shi$). Since $shibire$ has already been named and $par$ is just a temporary name, we preferably write the outcome of the cross as $\frac{shi^-}{shi^-}$ instead of $\frac{par^-}{shi^-}$. If $par^-$ and $shi^-$ complement, this means we can think of the parents in Figure {{ref>Fig3}} as having the genotypes $\frac{par^-}{par^-} \cdot \frac{shi^+}{shi^+}$ and $\frac{par^+}{par^+} \cdot \frac{shi^-}{shi^-}$. On the other hand, if $par^-$ and $shi^-$ do not complement, this implies that $par^-$ and $shi^-$ are mutant in the same gene (i.e., $par = shi$). Since $shibire$ has already been named and $par$ is just a temporary name, we preferably write the outcome of the cross as $\frac{shi^-}{shi^-}$ instead of $\frac{par^-}{shi^-}$.
-===== Mendel's First Law of Segregation =====+===== Mendel's First Law of Segregation (monohybrid cross) =====
  
  
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 This actually constitutes our second definition of a gene: genes are units of inheritance that follow Mendel's Laws. A phenotype is determined by a single gene if it displays a 3:1 dominant to recessive ratio in a monohybrid cross. Historically, this was the first and original definition of a gene developed by Gregor Mendel in the 1860s. Mendel was able to detect gene segregation of single genes in pea plants because he looked at simple traits and started with true breeding strains. That genes with two alleles segregate in this way is often described as Mendel's First Law.  This actually constitutes our second definition of a gene: genes are units of inheritance that follow Mendel's Laws. A phenotype is determined by a single gene if it displays a 3:1 dominant to recessive ratio in a monohybrid cross. Historically, this was the first and original definition of a gene developed by Gregor Mendel in the 1860s. Mendel was able to detect gene segregation of single genes in pea plants because he looked at simple traits and started with true breeding strains. That genes with two alleles segregate in this way is often described as Mendel's First Law. 
  
-===== Mendel's Second Law of Independent Assortment =====+===== Mendel's Second Law of Independent Assortment (dihybrid cross) =====
  
  
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 <table Tab3> <table Tab3>
 ^  F2 phenotypes  ^  $p$($shi$ phenotype)  ^  $p$($vg$ phenotype)  ^  p(combined)  ^ ^  F2 phenotypes  ^  $p$($shi$ phenotype)  ^  $p$($vg$ phenotype)  ^  p(combined)  ^
-|  normal movement, normal wings  |  $\frac{3}{4}$  |  $\frac{3}{4}$  |  $\frac{3}{5} \times \frac{3}{4}=\frac{9}{16}$  |+|  normal movement, normal wings  |  $\frac{3}{4}$  |  $\frac{3}{4}$  |  $\frac{3}{4} \times \frac{3}{4}=\frac{9}{16}$  |
 |  paralyzed, normal wings  |  $\frac{1}{4}$  |  $\frac{3}{4}$  |  $\frac{1}{4} \times \frac{3}{4}=\frac{3}{16}$  | |  paralyzed, normal wings  |  $\frac{1}{4}$  |  $\frac{3}{4}$  |  $\frac{1}{4} \times \frac{3}{4}=\frac{3}{16}$  |
 |  normal movement, vestigial wings  |  $\frac{3}{4}$  |  $\frac{1}{4}$  |  $\frac{3}{4} \times \frac{1}{4}=\frac{3}{16}$  | |  normal movement, vestigial wings  |  $\frac{3}{4}$  |  $\frac{1}{4}$  |  $\frac{3}{4} \times \frac{1}{4}=\frac{3}{16}$  |
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 |  paralyzed and vestigial wings (recombinant)  |  $\frac{shi}{shi} \cdot \frac{vg}{vg}$  |  $(\frac{1}{4} \times 1)=\frac{1}{4}$  | |  paralyzed and vestigial wings (recombinant)  |  $\frac{shi}{shi} \cdot \frac{vg}{vg}$  |  $(\frac{1}{4} \times 1)=\frac{1}{4}$  |
 |  normal (recombinant)  |  $\frac{shi}{+} \cdot \frac{vg}{+}$  |  $(\frac{1}{4} \times 1)=\frac{1}{4}$  |  |  normal (recombinant)  |  $\frac{shi}{+} \cdot \frac{vg}{+}$  |  $(\frac{1}{4} \times 1)=\frac{1}{4}$  | 
-|  vestigial wings (parental)  |  $\frac{shi}{+} \cdot \frac{vg}{+}$  |  $(\frac{1}{4} \times 1)=\frac{1}{4}$  | +|  vestigial wings (parental)  |  $\frac{shi}{+} \cdot \frac{vg}{vg}$  |  $(\frac{1}{4} \times 1)=\frac{1}{4}$  | 
 <caption> <caption>
 A test cross, Drosophila style. The term parental means that the F2 phenotypes resemble those of the parents in Cross 3.4, whereas recombinant means that it is different than those parents. Other synonyms for recombinant include non-parental and crossover class (see [[chapter_05|Chapter 05]]). A test cross, Drosophila style. The term parental means that the F2 phenotypes resemble those of the parents in Cross 3.4, whereas recombinant means that it is different than those parents. Other synonyms for recombinant include non-parental and crossover class (see [[chapter_05|Chapter 05]]).
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 For now, it seems like regardless of whether you look at it from a 9:3:3:1 "dihybrid cross" perspective or a 1:1:1:1 "test cross" perspective, Mendel's Second Law is not as useful as Mendel's First Law. The First Law gives you information about whether a mutant phenotype is caused by mutation in a single gene – this seems to be useful. The Second Law appears to describe a phenomenon (alleles for different genes segregate independently of each other) but doesn't seem to give useful information about the genes themselves. In Chapters [[chapter_04|04]] and [[chapter_05|05]], you will see that the ideas underlying the Second Law set the stage for understanding linkage, which provide a new definition of genes based on position.  For now, it seems like regardless of whether you look at it from a 9:3:3:1 "dihybrid cross" perspective or a 1:1:1:1 "test cross" perspective, Mendel's Second Law is not as useful as Mendel's First Law. The First Law gives you information about whether a mutant phenotype is caused by mutation in a single gene – this seems to be useful. The Second Law appears to describe a phenomenon (alleles for different genes segregate independently of each other) but doesn't seem to give useful information about the genes themselves. In Chapters [[chapter_04|04]] and [[chapter_05|05]], you will see that the ideas underlying the Second Law set the stage for understanding linkage, which provide a new definition of genes based on position. 
  
-Historically, Mendel's First and Second Laws also set the stage for chromosome theory, which we discuss in [[chapter_04|Chapter 04]]. Chromosomes behave in meiosis the same way that Mendel showed genes to behave. This is a now  good time to review [[chapter_01|Chapter 01]]. Each gamete receives only one of the two homologous chromosomes from its mother cell, a behavior that is analogous to segregation of alleles of a single gene (Mendel's First Law). Furthermore, the relative orientation of different homologous chromosome pairs (tetrads) at the first meiotic cell division is random, which is analogous to independent assortment of two different genes (Mendel's Second Law). To scientists in the early 20th century when chromosomes were just recently discovered and Mendel was just being re-discovered, this correlation strongly suggested that genes are physically located on chromosomes. In [[chapter_04|Chapter 04]], we will see the experimental evidence that supported this idea.+Historically, Mendel's First and Second Laws also set the stage for chromosome theory, which we discuss in [[chapter_04|Chapter 04]]. Chromosomes behave in meiosis the same way that Mendel showed genes to behave. This is now a good time to review [[chapter_01|Chapter 01]]. Each gamete receives only one of the two homologous chromosomes from its mother cell, a behavior that is analogous to segregation of alleles of a single gene (Mendel's First Law). Furthermore, the relative orientation of different homologous chromosome pairs (tetrads) at the first meiotic cell division is random, which is analogous to independent assortment of two different genes (Mendel's Second Law). To scientists in the early 20th century when chromosomes were just recently discovered and Mendel was just being re-discovered, this correlation strongly suggested that genes are physically located on chromosomes. In [[chapter_04|Chapter 04]], we will see the experimental evidence that supported this idea.
  
-You might also are wondering at this point: what if two genes happen to be on the same chromosome? We address this later in Chapters [[chapter_04|04]] and [[chapter_05|05]]. Mendel got lucky - the genes he chose to study were all unlinked to each other. If he had chosen genes that were linked to each other (closely positioned on the same chromosome) he may not have been able to draw the same conclusions that he did regarding his Second Law. +You might also be wondering at this point: what if two genes happen to be on the same chromosome? We address this later in Chapters [[chapter_04|04]] and [[chapter_05|05]]. Mendel got lucky - the genes he chose to study were all unlinked to each other. If he had chosen genes that were linked to each other (closely positioned on the same chromosome) he may not have been able to draw the same conclusions that he did regarding his Second Law. 
  
 ===== Application of Mendel's Laws to a modern problem ===== ===== Application of Mendel's Laws to a modern problem =====
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-If you revisit [[chapter_01|Chapter 01]] at this time, you will see that both Mendel's First and Second Laws relate directly to meiosis. The patterns of allele segregation as described by Mendel match nearly perfectly with the patterns of chromosome segregation in meiosis. It is very important for students of genetics to know that Mendel's view of genetics helps us understand the relationship between segregation patterns of genes and meiosis. However, it is equally important for students to realize that Mendel made these discoveries in the 1860s, and in many ways Mendel's Laws are very outdated both in terms of their conclusions and how they are described. In fact, continuing to call his discoveries "Laws" is a misnomer reflecting a great deal of European cultural bias; his view of heredity is much too simplistic, and there are many exceptions to Mendel's Laws as he described them, such as linkage, co-dominance, epistasis, epigenetic inheritance, allelic series, etc., most of which we don't cover in detail in this book (many of these concepts make more sense once you stop thinking like Mendel and start thinking about genes from a molecular perspective anyway). Once you reach [[chapter_06|Chapter 06]], it's important to relate everything you learn about genetics to the physical definition of a gene and chromosomes, rather than view Mendel as dogma. View Mendel as a beginner’s learning tool instead.+If you revisit [[chapter_01|Chapter 01]] at this time, you will see that both Mendel's First and Second Laws relate directly to meiosis. The patterns of allele segregation as described by Mendel match nearly perfectly with the patterns of chromosome segregation in meiosis. It is very important for students of genetics to know that Mendel's view of genetics helps us understand the relationship between segregation patterns of genes and meiosis. However, it is equally important for students to realize that Mendel made these discoveries in the 1860s, and in many ways Mendel's Laws are very outdated both in terms of their conclusions and how they are described. In fact, continuing to call his discoveries "Laws" is a misnomer reflecting a great deal of European cultural bias; his view of heredity is much too simplistic, and there are many exceptions to Mendel's Laws as he described them, such as linkage, codominance, epistasis, epigenetic inheritance, allelic series, etc., most of which we don't cover in detail in this book (many of these concepts make more sense once you stop thinking like Mendel and start thinking about genes from a molecular perspective anyway). Once you reach [[chapter_06|Chapter 06]], it's important to relate everything you learn about genetics to the physical definition of a gene and chromosomes, rather than view Mendel as dogma. View Mendel as a beginner’s learning tool instead.
  
 ===== Questions and exercises ===== ===== Questions and exercises =====
chapter_03.1724740284.txt.gz · Last modified: 2024/08/26 23:31 by mike