For example, as few as five to six VH genes can make up 50% of the rearrangements, whereas ∼60% of the functional genes (24 of 39) are expressed with over 1% frequency ( 6– 8). Analysis of Ab genes amplified from diverse sources indicates a strong bias in gene usage. However, the precise molecular mechanisms that govern its expression remain incompletely understood. Recent studies of the human repertoire have improved our understanding of its genomic complexity. The data indicate that the environment in which B cells develop can affect the expressed Ig repertoire by exerting influences on the distribution of expressed VH and VL genes and by influencing the amino acid composition of the Ag binding site. Amino acids in the CDRH3s in both species showed positive selection of tyrosines and glycines, and negative selection of leucines. Even the CDRH3s in the productive rearrangements were shorter in length than those of the normal human productive repertoire. Notably, nonproductive human VH rearrangements in the transgenic mice expressed shorter CDRH3 with less N addition. Gene selection differences were also noted in L chains. Although expression of some VH genes was similar in mouse and human (IGHV3-23, IGHV3-30, and IGHV4-59), other genes behaved differently (IGHV3-33, IGHV3-48, IGHV4-31, IGHV4-34, and IGHV1-18). However, differences between the distribution of nonproductive and productive rearrangements that reflect the impact of selection suggested species-specific selection played a role in shaping the respective repertoires. ![]() By examining the nonproductive repertoire as an indication of the immediate product of the rearrangement machinery without an impact of selection, we discovered that the distribution of human rearrangements arising in the mouse was generally comparable to that seen in humans. To determine the impact of the milieu on the development of the human B cell repertoire, we carried out a comprehensive analysis of productive and nonproductive Ig gene rearrangements from transgenic mice engineered to express single copies of the unrearranged human H chain and L chain Ig gene loci.
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