Basic Principles of Human Genetics: DNA Structure and Function - Prof. Salas, Monografías, Ensayos de Medicina

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PART ONE

Basic Principles of

Human Genetics

INTRODUCTION

The 20th century will likely be remembered by historians of biological science for the discov- ery of the structure of DNA and the mechanisms by which information coded in DNA is trans- lated into the amino acid sequence of proteins. Although the story of modern human genetics begins about 50 years before the structure of DNA was elucidated, we will start our exploration here. We do so because everything we know about inheritance must now be viewed in the light of the underlying molecular mechanisms. We will see here how the structure of DNA sets the stage both for its replication and for its ability to direct the synthesis of proteins. We will also see that the function of the system is tightly regulated, and how variations in the struc- ture of DNA can alter function. The story of human genetics did not begin with molecular biology, and it will not end there, as knowledge is now being integrated to explain the behav- ior of complex biological systems. Molecular biology, however, remains a key engine of progress in biological understanding, so it is fitting that we begin our journey here.

DNA Structure and Function

KEY POINTS

• DNA consists of a double helical sugar-phosphate structure with the two strands held together by hydrogen bonding between adenine and thymine or cytosine and guanine bases.
• DNA replication involves local unwinding of the double helix and copying a new strand from the base sequence of each parental strand. Replication proceeds bidirectionally from multiple start sites in the genome.
• DNA is complexed with proteins to form a highly compacted chromatin fiber in the nucleus.
• Genetic information is copied from DNA into messenger RNA in a highly regulated process that involves activation or repression of individual genes. mRNA molecules are extensively processed in the nucleus, including removal of introns and splicing together of exons, prior to export to the cytoplasm for translation into protein.
• The base sequence of mRNA is read in triplet codons to direct the assembly of amino acids into protein on ribosomes.
• Some genes are permanently repressed by methylation of some cytosine bases. These include most genes on one of two X chromosomes in cells of females and one of the two copies of genes that are said to be imprinted.

DEOXYRIBONUCLEIC ACID

Mendel described dominant and recessive inheritance before the concept of the “gene” was introduced, and long before the chemical basis of inheritance was known. Cell biologists during the late 19th and early 20th centuries had established the cell nucleus as the likely location of the genetic material, and DNA was long known to be a major chemical constituent. As the chemistry of DNA came to be understood, for a long time it was considered to be too simple a molecule – consisting of just four chemical building blocks, the bases adenine, guanine,

The strands are bound together by hydrogen bonds between adenine and thymine bases and between guanine and cytosine bases. Together these strands form a double helix. The two strands run in opposite (antiparallel) directions, so that one extends 5′ to 3′ while the other goes 3′ to 5′. The key feature of DNA, wherein resides its ability to encode information, is in the sequence of the four bases (Methods 1.2). The number of adenine bases (A) always equals the number of thymines (T), and the number of cytosines (C) always equals the number of guanines (G). This is because A on one strand is always paired with T on the other, and C on one strand is always paired with G. The pairing is noncovalent, due to hydrogen bonding between com- plementary bases. G–C base pairs form three hydrogen bonds, whereas A–T pairs form two, making the G–C pairs slightly more thermodynamically stable. Because the pairs always include one purine base (A or G) and one pyrimidine base (C or T), the distance across the helix remains constant.

DNA Replication

The complementarity of A to T and G to C provides the basis for DNA replication, a point that was recognized by Watson and Crick in their paper describing the structure of DNA. DNA replication proceeds by a localized unwinding of the double helix, with each strand serving as a template for replication of a new sister strand (Figure 1.2). Wherever a G base is found on one strand a C will be placed on the growing strand; wherever a T is found an A will be placed, etc. Bases are positioned in the newly synthesized strand by hydrogen bonding, and new phos- phodiester bonds are formed in the growing strand by action of the enzyme DNA polymerase. This is referred to as semiconservative replication, because the newly synthesized DNA double helices are hybrid molecules that consist of one parental strand and one new “daughter” strand. Unwinding of the double helix is accomplished by another enzyme system, called helicase. DNA replication requires growth of a strand from a pre-existing “primer” sequence. The primer sequences are provided by a process of transcription, in which a short RNA molecule is synthesized from the DNA template. We will focus on transcription in the next section when we look at the means by which genetic information is used to synthesize protein. RNA is a single- stranded nucleic acid, similar to DNA, except that the sugar molecules are ribose rather than deoxyribose, and uracil substitutes for thymine (and pairs with adenine). These short RNA primers are extended by DNA polymerase (Figure 1.3). DNA is synthesized in a 5′ (exposed phos- phate on 5′ carbon of the ribose molecule) to 3′ (exposed hydroxyl on the 3′ carbon) direction.

4 CHAPTER 1 DNA Structure and Function

Methods 1.

Isolation of DNA

DNA, or in some cases RNA, is the starting point for most experiments aimed at study of gene struc- ture or function. DNA can be isolated from any cell that contains a nucleus. The most commonly used tissue for human DNA isolation is peripheral blood, where white blood cells provide a readily accessible source of nucleated cells. Other commonly used tissues include cultured skin fibroblasts, epithelial cells scraped from the inner lining of the cheek and fetal cells obtained by amniocentesis or chorionic villus biopsy. Peripheral blood lymphocytes can be transformed with Epstein–Barr virus into immortalized cell lines, providing permanent access to growing cells from an individual. Nuclear DNA is complexed with proteins, which must be removed in order for the DNA to be analyzed. For some experiments it is necessary to obtain highly purified DNA, which involves digestion or removal of the proteins. In other cases, relatively crude preparations suffice. This is the case, for example, with DNA isolated from cheek scrapings. The small amount of DNA isolated from this source is usually released from cells with minimal effort to remove proteins. This preparation is adequate for limited analysis of specific gene sequences. Crude DNA preparations can be obtained from very minute biological specimens, such as drops of dried blood, skin cells, or hair samples isolated from crime scenes for forensic analysis. Isolation of RNA involves purification of nucleic acid from the nucleus and/or cytoplasm. This RNA can be used to study the patterns of gene expression in a particular tissue. RNA tends to be less stable than DNA, requiring special care during isolation to avoid degradation.

How are DNA molecules replicated?

?

For one strand, referred to as the leading strand, this can be accomplished continuously as the DNA unwinds. The other strand, called the lagging strand, is replicated in short segments, called Okazaki fragments, which are then enzymatically ligated together by DNA ligase. Two distinct polymerases, δ (leading strand) and α (lagging strand) replicate the DNA. The short RNA primers are ultimately removed and replaced with DNA to complete the replication process. The human genome consists of over 3 billion base pairs of DNA packaged onto 23 pairs of chromosomes. Each chromosome consists of a single, continuous DNA molecule, encompass- ing tens to hundreds of millions of base pairs. If the DNA on each chromosome were to be repli- cated in a linear manner from one end to another the process would go on interminably – certainly too long to sustain the rates of cell division that must occur. In fact, the entire genome can be replicated in a matter of hours because replication occurs simultaneously at multiple sites along a chromosome. These origins of replication are bubble-like structures from which DNA replication proceeds bidirectionally until an adjacent bubble is reached (Figure 1.4).

CHAPTER 1 DNA Structure and Function 5

Figure 1.2 • DNA replication involves local unwinding of the double helix and copying of two daughter strands from the original parental strands.

Structure of a replication fork

DNA ligase

Old RNA primer

Okazaki fragment (^5) ′

5 ′

3 ′

3 ′

Lagging strand template

DNA polymerase α

DNA polymerase δ

DNA primase subunit New RNA primer Single strand DNA binding protein

Leading strand template

DNA helicase Parental DNA

Figure 1.3 • DNA replication proceeds in a 5 ′ to 3′ direction. This occurs by direct addition of bases to a growing DNA strand in one direction (bottom). In the other direction, replication begins with creation of short RNA primers. DNA bases are added to the primers, and short seg- ments, called Okazaki fragments, are ligated together. The DNA at the replica- tion fork is unwound by a helicase enzyme. From Pritchard & Korf (2003) Medical Genetics at a Glance. Blackwell Publishing, Oxford.

CHAPTER 1 DNA Structure and Function 7

■ Dyskeratosis congenita

Eddy is a 4-year-old boy brought in by his parents because of recurrent cough. He has had two bouts of pneumonia, which were treated with antibiotics, over the past 2 months. Now he is sick again, having never stopped coughing since the last episode of pneu- monia. He has also been noted by his parents to have lacked energy over the past several weeks. His examination shows a fever of 39°C and rapid respirations with frequent coughing. His breath sounds are abnormal on the right side of his chest. He also has hyper- keratotic skin with streaky hyperpigmentation. His finger and toe nails are thin and broken at the ends and his hair is sparse. A blood count shows anemia and a reduced number of white blood cells. A bone marrow aspirate is obtained, and it shows a generalized decrease in all cell lineages. A clinical diagnosis of dyskeratosis congenita is made.

Dyskeratosis congenita consists of reticulated hyperpigmentation of the skin, dystrophic hair and nails, and generalized bone marrow failure (Figure 1.6). It usually presents in childhood, often with signs of pancytopenia. There is an increased rate of spontaneous chromosome breakage seen in peripheral blood lymphocytes. Dyskeratosis congenita can be inherited as an X-linked recessive (MIM 305000), autosomal dominant (MIM 127550), or autosomal recessive (MIM 224230) trait. The X-linked form is due to mutation in a gene that encodes the protein dyskerin (MIM 300126). Dyskerin is involved in the synthesis of ribosomal RNA and also interacts with telomerase. The autosomal dominant form is due to mutation in the gene hTERC (MIM 602322). hTERC encodes the RNA component of telomerase. The gene encoding the autosomal recessive form is not yet known. The X-linked recessive form is more severe and earlier in onset than the dominant form. Both forms are associated with defective telomere functioning, leading to shortened telom- eres. This likely leads to premature cell death and also explains the spontaneous chromosome breakage. The phenotype of the X- linked form may also be due, in part, to defective rRNA processing.

CLINICAL SNAPSHOT 1.

Figure 1.6 • Skin changes in an individual with dyskeratosis congenita. [Reproduced with permission from T. Burns, S. Breathnach, N. Cox, and C. Griffiths, eds, 7th edn, Rook’s Textbook of Dermatology, Blackwell Publishing, Oxford.]

RNA sequence in the enzyme; for humans the sequence is GGGTTA. Each chromosome end has a tandem repeat of thousands of copies of the telomere sequence that is replicated during early development. Somatic cells may replicate without telomerase activity, resulting in a gradual shortening of the ends of the chromosomes with successive rounds of replication. This may be one of the factors that limits the number of times a cell can divide before it dies, a phenomenon known as senescence (Clinical Snapshot 1.1).

Chromatin

The DNA within each cell nucleus must be highly compacted to accommodate the entire genome in a very small space. The enormous stretch of DNA that composes each chromosome is actually a highly organized structure (Figure 1.7). The DNA double helix measures approx-

How is DNA packaged in the cell nucleus?

?

imately 2 nm in diameter, but DNA does not exist in the nucleus in a “naked” form. It is com- plexed with a set of lysine- and arginine-rich proteins called histones. Two molecules of each of four major histone types – H2A, H2B, H3, and H4 – associate together with about every 146 base pairs to form a structure known as the nucleosome, which results in an 11-nm thick fiber. Nucleosomes are separated from one another by up to 80 base pairs, like beads on a string. This is more or less the conformation of actively transcribed chromatin but, during periods of inactivity, some regions of the genome are more highly compacted. The next level of organization is the coiling of nucleosomes into a 30-nm thick chromatin fiber held together by another histone, H1, and other nonhistone proteins. Chromatin is further compacted into the highly condensed structures comprising each chromosome, with the maximum condensa- tion occurring during the metaphase stage of mitosis (see Chapter 6).

GENE FUNCTION

The basic tenet of molecular genetics – often referred to as “the central dogma”—is that DNA encodes RNA, which in turn encodes the amino acid sequence of proteins. It is now clear that this is a simplified view of the function of the genome. As will be seen in Chapter 4, much of the DNA sequence does not encode protein. A large proportion of the genome consists of non- coding sequences, such as repeated DNA, or encodes RNA that is not translated into protein. Nevertheless, the central dogma remains a critical principle of genome function. We will explore here the flow of information from DNA to RNA to protein.

Transcription

The process of copying the DNA sequence of a gene into messenger RNA (mRNA) is referred to as transcription. Some genes are expressed nearly ubiquitously. These are referred to as house- keeping genes. They include genes necessary for cell replication or metabolism. For other genes, expression is tightly controlled, with particular genes being turned on or off in particular cells at specific times in development or in response to physiological signals. Gene expression is regulated by proteins that bind to DNA and either activate or repress

8 CHAPTER 1 DNA Structure and Function

2 nm

11 nm

30 nm

H2A-H2B-H3-H H2A-H2B-H3-H histone octomer

Figure 1.7 • Levels of organization of chromatin. The DNA double helix has a width of approximately 2 nm. The funda- mental unit of chromatin is the nucleo- some, which consists of 146 base pairs of DNA wound around a core consisting of two copies of each of the four histone pro- teins (H2A, H2B, H3, and H4). These are arrayed as beads on a string. The diame- ter of a nucleosome is 11 nm. The nucleo- somes are, in turn, wound into a structure measuring 30 nm. This is further coiled and condensed to compose a metaphase chromosome.

What is the role of RNA in conveying the sequence of DNA from the nucleus to the cytoplasm?

?

be under a hundred bases long, whereas introns can be several thousand bases in length. Therefore, much of the length of a gene may be devoted to noncoding introns. The number of exons in a gene may be as few as one or two, or may number in the dozens. The process- ing of the RNA transcript into mature mRNA requires the removal of the introns and splicing together of the exons (Figure 1.10). This is carried out by an enzymatic process that occurs in the nucleus. The 5′ end of an intron always consists of the two bases GU, following by a con-

10 CHAPTER 1 DNA Structure and Function

Transcription by RNA polymerase II

5 ′

5 ′

5 ′

5 ′

5 ′

5 ′ 5 ′

5 ′

5 ′ 5 ′ 5 ′

3 ′

3 ′

3 ′

3 ′ 3 ′

3 ′

3 ′

3 ′

DNA

TATA box

Template

Coding Pol II

TATAAA

RNA transcript

Transcription initiation site

Initiation of transcription

Elongation of transcript

Polyadenylation

MeG

AGUCATCAGT

AGTCA

AAUAA

AATAA Polyadenylation signal GCAAAAAAA

Waste RNA

Transcription termination signal?

‘Transcription bubble’ Polyadenylation site

GCCG

CodingTemplate

CodingTemplate

Figure 1.9 • Transcription involves copying an RNA from one stand of DNA. The reaction is catalyzed by RNA poly- merase. A 7-methylguanosine cap (MeG) is added to the 5′ end of most mRNA mol- ecules before transcription is completed. From Pritchard & Korf (2003) Medical Genetics at a Glance. Blackwell Publishing, Oxford.

Intron excision and exon splicing

RNA lariat

Nuclear membrane

GU A AG

GU A AG

5 ′ 3 ′

5 ′ (^3) ′

Exon 1 Intron Exon 2

Exon 1 Exon 2

Donor site Branch site Acceptor site

1 2

U

U

U

AA

A

G G

U

GAA G

U

1 5

Spliceosome

Cut Cut

hnRNA

mRNA

Figure 1.10 • RNA splicing begins with binding of specific ribonucleoproteins (U1 and U2) to the splice donor and acceptor. These two sites are then brought together by other components of the splicosome. The donor site is then cut and the free end of the intron binds to the branch point within the intron to form a lariat structure. Then the acceptor site is cleaved, releasing the lariat, and the exons at the two ends are ligated together. From Pritchard & Korf (2003) Medical Genetics at a Glance. Blackwell Publishing, Oxford.

sensus sequence that is similar, but not identical, in all introns. This is the splice donor. The 3′ end, the splice acceptor, ends in AG, preceded by a consensus sequence. The splicing process requires a complex machinery comprised of both proteins and small RNA molecules (small nuclear RNA, or snRNA), consisting of fewer than 200 bases. snRNA is also transcribed by RNA polymerase II. The splice is initiated by binding of a protein–RNA complex to the splice donor, at a point within the intron called the branch point, and the splice acceptor. First the DNA is cleaved at the donor site and this is attached in a 5′–2′ bond to the branch point. Then the acceptor site is cleaved, releasing a lariat structure that is subsequently degraded, and the 5′ and 3′ ends are ligated together. The splicing process also requires the function of proteins, SR proteins, which are involved in selecting sites for the initiation of splicing. These proteins interact with sequences known as splice enhancers or silencers. The splicing process is vulnerable to disruption by mutation, as might be predicted from its complexity. The RNA splicing process offers a point of control of gene expression. Under the influence of control molecules present in specific cells, particular exons may be included or not included in the mRNA due to differential splicing (Figure 1.11). This results in the potential to produce multiple, different proteins from the same gene, adding greatly to the diversity of proteins encoded by the genome. Specific exons may correspond with particular functional domains of proteins, leading to the production of multiple proteins with diverse functions from the same gene. Some mRNAs are subject to RNA editing, in which a specific base may be enzymatically modified. For example, the protein apolipoprotein B exists in two forms, a 48-kDa form made in the intestine and a 100-kDa form in the liver. Both forms are the product of the same gene. In the intestine, however, the enzyme cytidine deaminase alters a C to a U at codon 2153, changing the codon from CAA (encoding glutamine) to UAA (a stop codon). This truncates the peptide, accounting for the 48-kDa form. Recently, another mechanism of post-transcritional regulation, called RNA interference, has also been identified (Hot Topics 1.1).

Translation

The mature mRNA is exported to the cytoplasm for translation into protein. During transla- tion, the mRNA sequence is read into the amino acid sequence of a protein (Figure 1.13). The translational machinery consists of a protein–RNA complex called the ribosome. Ribosomes consist of a complex of proteins and specialized ribosomal RNA molecules (rRNA). The eukary- otic ribosome is comprised of two subunits, designated 60S and 40S (the “S” is a measure- ment of density, the Svendborg unit, reflecting how the complexes were initially characterized).

CHAPTER 1 DNA Structure and Function 11

A B C D E F

A B C D E F

A B D E F

Figure 1.11 • Alternative splicing. Splicing out each intron results in inclusion of exons A–F in the mRNA. Alternatively, a splice can be made directly between exons B and D, skipping exon C. This results in production of a distinct protein, missing the amino acids encoded by exon C.

How is mRNA translated into protein?

?

Hot Topic 1.1 R N A I N T E R F E R E N C E continued

CHAPTER 1 DNA Structure and Function 13

Cytoplasm Nucleus

Primary miRNA transcript

Drosha

miRNA precursor

siRNA

RISC miRNP

7mG AAAA 7mG AAAA

mRNA cleavage Translational repression

Experimental system viral RNA

Dicer ATP DCR-

Figure 1.12 • Mechanisms of RNA interference. dsRNA may be introduced by viral infection or experimentally. siRNA is produced from dsRNA through cleavage by the enzyme Dicer. Single-stranded siRNA complexes with proteins to form the RISC, which then binds to mRNA through homologous pairing with the siRNA and cleaves the mRNA. Endogenous miRNA is transcribed and cleaved into hairpin structures in the nucleus. These are exported to the cytoplasm, where they are processed into miRNA by Dicer. The miRNA complexes with proteins and binds to mRNA, often in the 3′ UTR, and inhibits translation. (Adapted by permission from Macmillan Publishers Ltd: Meister G, Tuschl T. Mechanisms of gene silencing by double-stranded RNA. Nature 2004;431:343–349.)

Gene Inactivation and Imprinting

Individual genes may be reversibly activated or repressed, but there are some situations where genes or sets of genes are permanently silenced. This occurs on one of the two copies of the X chromosome in females, and on the maternal or paternal copy of a set of genes that are said to be imprinted. Gene silencing is accompanied by methylation of cytosine bases to

14 CHAPTER 1 DNA Structure and Function

Translation

5 ′ 3 ′ 5 ′ 3 ′

Initiation (i) (ii)

(iii) (iv)

(v) (vi)

(viii) (ix)

(vii)

Elongation

Termination

Cap

Me-G

AUG Me-G

AUG

N C N C

MET (^) MET

N C

MET

N C

MET

N N METC C

LEU N C

LEU

N C MET N C LEU

N C

MET

N C

LEU

UAC

UGA

UACAUG

UCUAGA UGAACUUAA UCUAGA ACUUAA

AUGUAC UACAUGCUG

GACCUG

GAC

UACAUG GACCUG

AUG GACCUGGCG

P

A P A

Initiation factors

UAC

UAC

C

ARG ARG THR THR

N C

C

C

N

C N

C SER (^) SER N

CN

EF

RF

EF

Small ribosomal subunit

Large ribosomal subunit

Figure 1.13 • The process of protein translation. Translation takes place at the ribosome, which binds to the mRNA. Specific amino acyl tRNA molecules bind to the mRNA by base pair complementar- ity between a triplet codon on the mRNA and an anticodon on the tRNA. A peptide bond is formed between the growing peptide and the next amino acyl tRNA, transferring the growing peptide and elongating it by one amino acid. This con- tinues until a stop codon is reached. EF: elongation factor, RF: release factor. From Pritchard & Korf (2003) Medical Genetics at a Glance. Blackwell Publishing, Oxford.

How can genes be permanently inactivated?

?

Genomic imprinting involves the silencing of either the maternal or paternal copy of a gene during early development (Figure 1.17). Like X-chromosome inactivation, imprinting is prob- ably accomplished through methylation of specific chromosome regions. The methylation “imprint” is erased in germ cells, so the specific gene copy to be inactivated is always deter- mined by the parent of origin, regardless of whether that particular gene copy was active or inactive in the previous generation. Genomic imprinting appears to apply only to a small subset of genes, although the full extent of imprinting is not yet known.

16 CHAPTER 1 DNA Structure and Function

CpG GpC

CH 3

CH 3

CpG GpC

GpC

CpG

GpC

CpG

GpC

DNA replication

Methylation

CpG

CH 3

CpG

CH 3

CpG

CH 3

GpC CH 3

GpC CH 3

CH 3

CH 3

CH 3

Figure 1.15 • Cytosine residues adjacent to guanines may be methylated near the 5 ′ ends of some genes. When the DNA is replicated, only one strand will be methy- lated, but then an enzyme recognizes the single methylated strand and methylates the cytosines on the opposite strand.

X (^) m X (^) p

X (^) m Xp Xm X (^) p

Xm X (^) P Xm^ X^ P

Xm X (^) P

Xm X (^) P Xm XP

Xm XP Xm^ XP

Xm Xp Xm^ Xp

X (^) m X (^) p

Xm Xp X^ m X^ p

X (^) m X (^) p X^ m^ X^ p

Xm XP Xm^ XP

X (^) m X (^) P

X (^) m X (^) P X^ m X^ P

Xm XP X^ m^ X^ P

Xm X (^) p Xm^ X^ p

X (^) m X (^) p

Xm X (^) p X^ m Xp

Xm X (^) p X^ m^ X^ p

X (^) m Xp Xm Xp

Figure 1.16 • X chromosome inactivation. In the zygote, both the maternally and paternally derived X chromosomes ( Xm and Xp ) are active. Early in development, one of the two X chromosomes in each cell is inactivated (indicated as the dark chromosome). This X chromosome remains inactive in all the descendants of that cell.

CONCLUSION

More than half a century of research in molecular biology has resulted in a detailed picture of the mechanisms of gene structure and function. Much of the remainder of this book will be devoted to exploration of the implications of dysfunction at the level of the gene or groups of genes and their interactions with the environment. We will see also that genetics research is moving to a new level of integration of basic molecular mechanisms, towards formation of a picture of how entire cells and organisms function. It is important to realize, however, that some fundamental molecular mechanisms, such as the role of small RNAs and genomic imprinting, have been discovered only within the past decade or so. Even as the effort towards larger-scale integration goes forward, there remains much to be learned about the fundamen- tal molecular mechanisms at the level of the gene.

REVIEW QUESTIONS

1.1 The two strands of DNA separate when heated, and the temperature at which separation occurs is dependent on base content. Specifically, DNA with a higher proportion of G–C base pairs tends to “melt” at a higher temperature than molecules with a higher A–T content. Why is this?

1.2 What is the role of transcription in DNA replication?

1.3 Consider the gene sequence below. What is the base sequence of the mRNA that would be transcribed from this gene, and what is the amino acid sequence of the peptide that would be translated? 5 ′ – promoter – ATG GTT GAT AGT CGT TGC CGC GGG CTG TGA – 3′ 3 ′ – promoter – TAC CAA CTA TCA GCA ACG GCG CCC GAC ACT – 5′

CHAPTER 1 DNA Structure and Function 17

paternal copy not expressed

maternal copy expressed

Figure 1.17 • Concept of genomic imprinting. In this example, the paternally derived copy of a gene is not expressed, whereas the maternally inherited copy is expressed. The imprint is “reset” in the germ line, so that in the next generation, the active copy of the gene depends on the parent of origin, not on whether that copy was active in the parent.