Comparative Genomics and Diversifying Selection of the Clustered Vertebrate Protocadherin Genes

By Wu, Qiang | Genetics, March 2005 | Go to article overview

Comparative Genomics and Diversifying Selection of the Clustered Vertebrate Protocadherin Genes


Wu, Qiang, Genetics


ABSTRACT

To explain the mechanism for specifying diverse neuronal connections in the brain, Sperry proposed that individual cells carry chemoaffinity tags on their surfaces. The enormous complexity of these connections requires a tremendous diversity of cell-surface proteins. A large number of neural transmembrane protocadherin (Pcdh) proteins is encoded by three closely linked human and mouse gene clusters (α, β, and γ). To gain insight into Pcdh evolution, I performed comprehensive comparative cDNA and genomic DNA analyses for the three clusters in the chimpanzee, rat, and zebrafish genomes. I found that there are species-specific duplications in vertebrate Pcdh genes and that additional diversity is generated through alternative splicing within the zebrafish "variable" and "constant" regions. Moreover, different codons (sites) in the mammalian Pcdh ectodomains (ECs) are under diversifying selection, with some under diversity-enhancing positive Darwinian selection and others, including calcium-binding sites, under strong purifying selection. Interestingly, almost all positively selected codon positions are located on the surface of ECs 2 and 3. These diversified residues likely play an important role in combinatorial interactions of Pcdh proteins, which could provide the staggering diversity required for neuronal connections in the brain. These results also suggest that adaptive selection is an additional evolutionary factor for increasing Pcdh diversity.

AJ important mechanism to generate molecular diversity is through alternative splicing. A special form of alternative splicing uses multiple distinct first exons. Mammalian genomes contain a large number of alternatively spliced genes that have multiple "variable" first exons (ZHANG et al. 2004). The clustered Pcdh genes exemplify this type of alternative splicing that utilizes multiple variable first exons. About 60 similar human and mouse Pcdh genes are organized into three sequentially linked clusters, designated α, β, and oy (see Figure 1, A and C) (Wu et al. 2001). The α and ·γ clusters have a variable and "constant" genomic organization, similar to that of immunoglobulin (Ig) and T-cell receptor ( Tcr) gene clusters (Wu and MANIATIS 1999). Specifically, the variable region of the α cluster contains 15 and 14 highly similar exons in humans and mice, respectively. These variable exons are unusually large (^2.5 kb each) and are organized in a tandem array, which is followed by the constant region of three small exons, in both humans and mice (Figure 1, A and C). Similarly, the variable region of both the human and mouse "y clusters contains a tandem array of 22 large similar exons; while the "y constant region contains three small downstream exons in both species (Figure 1, A and C). In contrast to the α and "y clusters, the human and mouse β clusters contain 16 and 22 variable exons, respectively, but do not contain a constant region. Thus, each member of the human and mouse β clusters is a single-exon gene (Figure 1, A and C).

Each Pcdh variable exon is preceded by a distinct promoter (TASiC et al. 2002), and these promoters share a highly conserved core motif (Wu et al. 2001; NOONAN et al. 2003, 2004). Spécifie promoter activation transcribes a high-molecular-weight precursor RNA that extends through all of the downstream variable and constant exons. However, only the 5'-most variable exon is a's-spliced to the first constant exon to generate functional mRNAs (TASIC et al. 2002; WANG et al. 2002a). Pcdh α and "y proteins are generally located at synaptic junctions in the central nervous system (CNS) (KoHMURA et al. 1998; WANG et al. 2002b; PHILLIPS et al. 2003), where they may form combinatorial hetero-asinteractions (MuRATA et al. 2004) and specific homophilic fraws-interactions (UBATA et al. 1995). Because of their synaptic localization, unusual genomic organization, and characteristic cadherin domains, the Pcdh proteins have been proposed to provide molecular tags for the chemoaffinity hypothesis (SPERRY 1963; SHAPIRO and COLMAN 1999).

The rest of this article is only available to active members of Questia

Sign up now for a free, 1-day trial and receive full access to:

  • Questia's entire collection
  • Automatic bibliography creation
  • More helpful research tools like notes, citations, and highlights
  • Ad-free environment

Already a member? Log in now.

Notes for this article

Add a new note
If you are trying to select text to create highlights or citations, remember that you must now click or tap on the first word, and then click or tap on the last word.
One moment ...
Project items

Items saved from this article

This article has been saved
Highlights (0)
Some of your highlights are legacy items.

Highlights saved before July 30, 2012 will not be displayed on their respective source pages.

You can easily re-create the highlights by opening the book page or article, selecting the text, and clicking “Highlight.”

Citations (0)
Some of your citations are legacy items.

Any citation created before July 30, 2012 will labeled as a “Cited page.” New citations will be saved as cited passages, pages or articles.

We also added the ability to view new citations from your projects or the book or article where you created them.

Notes (0)
Bookmarks (0)

You have no saved items from this article

Project items include:
  • Saved book/article
  • Highlights
  • Quotes/citations
  • Notes
  • Bookmarks
Notes
Cite this article

Cited article

Style
Citations are available only to our active members.
Sign up now to cite pages or passages in MLA, APA and Chicago citation styles.

(Einhorn, 1992, p. 25)

(Einhorn 25)

1

1. Lois J. Einhorn, Abraham Lincoln, the Orator: Penetrating the Lincoln Legend (Westport, CT: Greenwood Press, 1992), 25, http://www.questia.com/read/27419298.

Cited article

Comparative Genomics and Diversifying Selection of the Clustered Vertebrate Protocadherin Genes
Settings

Settings

Typeface
Text size Smaller Larger
Search within

Search within this article

Look up

Look up a word

  • Dictionary
  • Thesaurus
Please submit a word or phrase above.
Print this page

Print this page

Why can't I print more than one page at a time?

Full screen

matching results for page

Cited passage

Style
Citations are available only to our active members.
Sign up now to cite pages or passages in MLA, APA and Chicago citation styles.

"Portraying himself as an honest, ordinary person helped Lincoln identify with his audiences." (Einhorn, 1992, p. 25).

"Portraying himself as an honest, ordinary person helped Lincoln identify with his audiences." (Einhorn 25)

"Portraying himself as an honest, ordinary person helped Lincoln identify with his audiences."1

1. Lois J. Einhorn, Abraham Lincoln, the Orator: Penetrating the Lincoln Legend (Westport, CT: Greenwood Press, 1992), 25, http://www.questia.com/read/27419298.

Cited passage

Welcome to the new Questia Reader

The Questia Reader has been updated to provide you with an even better online reading experience.  It is now 100% Responsive, which means you can read our books and articles on any sized device you wish.  All of your favorite tools like notes, highlights, and citations are still here, but the way you select text has been updated to be easier to use, especially on touchscreen devices.  Here's how:

1. Click or tap the first word you want to select.
2. Click or tap the last word you want to select.

OK, got it!

Thanks for trying Questia!

Please continue trying out our research tools, but please note, full functionality is available only to our active members.

Your work will be lost once you leave this Web page.

For full access in an ad-free environment, sign up now for a FREE, 1-day trial.

Already a member? Log in now.