Hybrid Vigor: Importance of Hybrid lambda Phages in Early Insights in Molecular Biology

Laboratory-generated hybrids between phage lambda and related phages played a seminal role in establishment of the lambda model system, which, in turn, served to develop many of the foundational concepts of molecular biology, including gene structure and control. Important lambda hybrids with phages 21 and 434 were the earliest of such phages. To understand the biology of these hybrids in full detail, we determined the complete genome sequences of phages 21 and 434. Laboratory-generated hybrids between phage lambda and related phages played a seminal role in establishment of the lambda model system, which, in turn, served to develop many of the foundational concepts of molecular biology, including gene structure and control. Important lambda hybrids with phages 21 and 434 were the earliest of such phages. To understand the biology of these hybrids in full detail, we determined the complete genome sequences of phages 21 and 434. Although both genomes are canonical members of the lambda-like phage family, they both carry unsuspected bacterial virulence gene types not previously described in this group of phages. In addition, we determined the sequences of the hybrid phages lambda imm21, lambda imm434, and lambda h434 imm21. These sequences show that the replacements of lambda DNA by nonhomologous segments of 21 or 434 DNA occurred through homologous recombination in adjacent sequences that are nearly identical in the parental phages. These five genome sequences correct a number of errors in published sequence fragments of the 21 and 434 genomes, and they point out nine nucleotide differences from Sanger's original lambda sequence that are likely present in most extant lambda strains in laboratory use today. We discuss the historical importance of these hybrid phages in the development of fundamental tenets of molecular biology and in some of the earliest gene cloning vectors. The 434 and 21 genomes reinforce the conclusion that the genomes of essentially all natural lambda-like phages are mosaics of sequence modules from a pool of exchangeable segments.